U.S. patent application number 12/393058 was filed with the patent office on 2009-09-10 for 2-aminoquinolines.
Invention is credited to Sabine Kolczewski, Claus Riemer, Olivier Roche, Lucinda Steward, Juergen Wichmann, Thomas Woltering.
Application Number | 20090227570 12/393058 |
Document ID | / |
Family ID | 40671014 |
Filed Date | 2009-09-10 |
United States Patent
Application |
20090227570 |
Kind Code |
A1 |
Kolczewski; Sabine ; et
al. |
September 10, 2009 |
2-AMINOQUINOLINES
Abstract
The present invention is concerned with 2-aminoquinoline
derivatives of formula I ##STR00001## where R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, A, and n are as defined in the
specification and claims, their use 5-HT.sub.5A receptor
antagonists, their manufacture, and pharmaceutical compositions
containing them.
Inventors: |
Kolczewski; Sabine;
(Loerrach, DE) ; Riemer; Claus; (Freiburg, DE)
; Roche; Olivier; (Folgensbourg, FR) ; Steward;
Lucinda; (Basel, CH) ; Wichmann; Juergen;
(Steinen, DE) ; Woltering; Thomas; (Freiburg,
DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
40671014 |
Appl. No.: |
12/393058 |
Filed: |
February 26, 2009 |
Current U.S.
Class: |
514/228.2 ;
514/235.2; 514/253.06; 514/313; 544/128; 544/363; 544/62;
546/159 |
Current CPC
Class: |
C07D 401/12 20130101;
A61P 1/00 20180101; C07D 405/14 20130101; C07D 451/14 20130101;
A61P 15/10 20180101; A61P 25/36 20180101; A61P 25/28 20180101; C07D
401/14 20130101; A61P 25/20 20180101; A61P 25/16 20180101; A61P
25/18 20180101; A61P 25/24 20180101; A61P 25/22 20180101; A61P
25/00 20180101; A61P 25/04 20180101 |
Class at
Publication: |
514/228.2 ;
546/159; 514/313; 544/363; 514/253.06; 544/128; 514/235.2;
544/62 |
International
Class: |
A61K 31/541 20060101
A61K031/541; C07D 215/38 20060101 C07D215/38; A61K 31/47 20060101
A61K031/47; C07D 401/12 20060101 C07D401/12; A61K 31/496 20060101
A61K031/496; C07D 413/12 20060101 C07D413/12; A61K 31/5377 20060101
A61K031/5377; A61K 31/4709 20060101 A61K031/4709; C07D 417/12
20060101 C07D417/12; A61P 25/24 20060101 A61P025/24; A61P 25/22
20060101 A61P025/22; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 5, 2008 |
EP |
08152327.6 |
Claims
1. A compound of formula (I) ##STR00025## wherein A is --CH.sub.2--
or --O--; R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen,
heterocycloalkyl, --(CH.sub.2).sub.a--R.sup.a, wherein R.sup.a is
hydrogen, alkoxy, hydroxy, cyano, or NR.sup.iR.sup.ii, wherein
R.sup.i and R.sup.ii are each independently hydrogen, alkyl or
C(O)O-alkyl, allyl, --C(NH)--S--R.sup.b, wherein R.sup.b is alkyl,
cycloalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, or alkenyl,
--C(NRC)NR.sup.dR.sup.e, wherein R.sup.c, R.sup.d, and R.sup.e are
each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl,
or wherein R.sup.d and R.sup.e together with the nitrogen to which
they are bound form a heterocycloalkyl, --C(O)R.sup.f, wherein
R.sup.f is alkyl, --(CH.sub.2).sub.b-cycloalkyl,
--(CH.sub.2).sub.b--Oalkyl, --(CH.sub.2).sub.b-heterocycloalkyl,
--O-heterocycloalkyl, or --(CH.sub.2).sub.b--NR.sup.iiiR.sup.iv,
wherein R.sup.iii and R.sup.iv are each independently hydrogen,
alkyl, --C(O)Oalkyl, --(CH.sub.2).sub.b-cycloalkyl,
--(CH.sub.2).sub.a--Oalkyl, bicyclic cycloalkyl, bicyclic
cycloalkenyl, --(CH.sub.2).sub.b-heterocycloalkyl,
--(CH.sub.2).sub.a--O-heterocycloalkyl, or
--(CH.sub.2).sub.a--NR'R'', wherein R' and R'' are each
independently hydrogen, alkyl or cycloalkyl,
--C(S)NR.sup.vR.sup.vi, wherein R.sup.v and R.sup.vi are each
independently H, alkyl or cycloalkyl,
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or heterocycloalkyl, or --S(O).sub.2-heterocycloalkyl,
or R.sup.1 and R.sup.2 together with the N atom to which they are
bound form a 5- or 6-membered heterocycloalkyl; R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are each independently selected from from the
group consisting of H, halo, alkyl, haloalkyl, hydroxyalkyl,
cyanoalkyl, alkoxy, haloalkoxy, --O-alkylene-O-alkyl, hydroxyl,
oxo, cyano, nitro and NR.sup.ixR.sup.x, wherein R.sup.ix and
R.sup.x are each independently H or alkyl; a is 1 to 6; b is 0 to
6; and n is 1 or 2, and wherein heterocycloalkyl is unsubstituted
or substituted with one or more substituents independently selected
from the group consisting of alkyl, hydroxy, hydroxyalkyl, benzyl,
oxo, --C(O)Oalkyl, cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl,
cyanoalkyl, alkylene-S(O).sub.2-alkyl,
-alkylene-C(O)N(alkyl).sub.2, halo, haloalkyl and alkyoxy; and
wherein cycloalkyl is unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
alkyl, hydroxy, hydroxyalkyl, phenyl, oxo,
cyanoalkyl,-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl,
halo, and alkyoxy; or a pharmaceutically acceptable salt
thereof.
2. The compound of claim 1, wherein a is 1 to 4.
3. The compound of claim 2, wherein a is 2.
4. The compound of claim 1, wherein b is 0 to 4.
5. The compound of claim 4, wherein b is 0 or 1.
6. The compound of claim 1, wherein R.sup.1 is hydrogen or
C.sub.1-4alkyl.
7. The compound of claim 6, wherein R.sup.1 is hydrogen.
8. The compound of claim 1, wherein R.sup.2 is hydrogen, 5- or
6-membered heterocycloalkyl, --(CH.sub.2).sub.a--R.sup.a, wherein
R.sup.a is hydrogen, alkoxy, hydroxy, cyano, or NR.sup.iR.sup.ii,
wherein R.sup.i and R.sup.ii are each independently hydrogen, alkyl
or C(O)O-alkyl, allyl, --C(NH)--S--R.sup.b, wherein R.sup.b is
alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, or alkenyl,
--C(NR.sup.c)NR.sup.dR.sup.e, wherein R.sup.c, R.sup.d, and R.sup.e
are each independently hydrogen, alkyl, cycloalkyl, 5- or
6-membered heterocycloalkyl, or wherein R.sup.d and R.sup.e
together with the nitrogen to which they are bound form a 5- or
6-membered heterocycloalkyl, --C(O)R.sup.f, wherein R.sup.f is
alkyl, --(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.b--Oalkyl,
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is a 5- or 6-membered monocycle or a 7-, 8- or 9-membered bicycle,
--O-heterocycloalkyl, wherein the heterocycloalkyl is a 5- or
6-membered monocycle, 10- or 11-membered spirocyclic
heterocycloalkyl, or --(CH.sub.2).sub.b-NR.sup.iiiR.sup.iv, wherein
R.sup.iii and R.sup.iv are each independently hydrogen, alkyl,
--C(O)Oalkyl, --(CH.sub.2).sub.b-cycloalkyl,
--(CH.sub.2).sub.a--Oalkyl, --(CH.sub.2).sub.a-NR'R'', wherein R'
and R'' are each independently hydrogen, alkyl or cycloalkyl, 7- or
8-membered bicyclic cycloalkyl or cycloalkenyl,
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is a 5- or 6-membered monocycle or a 7-, 8- or 9-membered bicycle,
or --(CH.sub.2).sub.a--O-heterocycloalkyl, wherein the
heterocycloalkyl is a 5- or 6-membered monocycle,
--C(S)NR.sup.vR.sup.vi, wherein R.sup.v and R.sup.vi are each
independently H, alkyl or cycloalkyl,
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or 5- or 6-membered heterocycloalkyl,
--S(O).sub.2-heterocycloalkyl, wherein the heterocycloalkyl is a 5-
or 6-membered monocycle or a 7-, 8- or 9-membered bicycle, or
--S(O).sub.2-spirocyclic heteroalkyl, wherein the spirocyclic
heteroalkyl is 10- or 11-membered; a is 1 to 6, b is 0 to 6, and
wherein heterocycloalkyl is unsubstituted or substituted with one
or more substituents independently selected from the group
consisting of alkyl, hydroxy, hydroxyalkyl, benzyl, oxo,
--C(O)Oalkyl, cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl,
cyanoalkyl, alkylene-S(O).sub.2-alkyl,
-alkylene-C(O)N(alkyl).sub.2, halo, haloalkyl and alkyoxy; and
wherein cycloalkyl is unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
alkyl, hydroxy, hydroxyalkyl, phenyl, oxo, cyanoalkyl,
-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl, halo, and
alkyoxy.
9. The compound of claim 1, wherein R.sup.2 is hydrogen, 6-membered
heterocycloalkyl, --(CH.sub.2).sub.a-NR.sup.iR.sup.ii, wherein
R.sup.i and R.sup.ii are each independently hydrogen, alkyl or
C(O)O-alkyl, allyl, --C(.dbd.NH)--S-alkyl
--C(.dbd.NR.sup.c)NR.sup.dR.sup.e, wherein R.sup.c, R.sup.d, and
R.sup.e are each independently hydrogen, alkyl, cycloalkyl,
6-membered heterocycloalkyl, or wherein R.sup.d and R.sup.e
together with the nitrogen to which they are bound form a
6-membered heterocycloalkyl, --C(O)R.sup.f, wherein R.sup.f is
alkyl, --(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.b--Oalkyl,
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is a 5- or 6-membered monocycle or a 7-membered bicycle, or
--O-heterocycloalkyl, wherein the heterocycloalkyl is a 6-membered
monocycle, 10-membered spirocyclic heterocycloalkyl,
--(CH.sub.2).sub.b-NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.a--Oalkyl,
7-membered bicyclic cycloalkyl,
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is a 5- or 6-membered monocycle or a 8- or 9-membered bicycle,
--(CH.sub.2).sub.a--O-heterocycloalkyl, wherein the
heterocycloalkyl is a 6-membered monocycle, or
--(CH.sub.2).sub.a-NR'R'', wherein R' and R'' are each
independently alkyl or cycloalkyl, --C(S)NH.sub.2,
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or 6-membered heterocycloalkyl,
--S(O).sub.2-heterocycloalkyl, wherein the heterocycloalkyl is a 5-
or 6-membered monocycle or a 7-membered bicycle, or
--S(O).sub.2-spirocyclic heteroalkyl, wherein the spirocyclic
heteroalkyl is 10- or 11-membered, a is 1 to 6, b is 0 to 6, and
wherein heterocycloalkyl is unsubstituted or substituted with one
or more substituents independently selected from the group
consisting of alkyl, hydroxy, hydroxyalkyl, benzyl, oxo,
--C(O)Oalkyl, cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl,
cyanoalkyl, alkylene-S(O).sub.2-alkyl,
-alkylene-C(O)N(alkyl).sub.2, halo, haloalkyl and alkyoxy; and
wherein cycloalkyl is unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
alkyl, hydroxy, hydroxyalkyl, phenyl, oxo, cyanoalkyl,
-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl, halo, and
alkyoxy.
10. The compound of claim 1, wherein R.sup.2 is hydrogen,
morpholin-4-yl, 4-methyl-piperazin-1-yl, or piperazin-1-yl,
--(CH.sub.2).sub.a--NR.sup.iR.sup.ii, wherein R.sup.i and R.sup.ii
are each independently hydrogen, alkyl or C(O)O-alkyl, allyl,
--C(.dbd.NH)--S-alkyl, --C(.dbd.NR.sup.c)NR.sup.dR.sup.e, wherein
R.sup.c is H or alkyl, and R.sup.d and R.sup.e are each
independently hydrogen, alkyl, cycloalkyl, 1-methyl-piperidin-4-yl,
piperidin-4-yl, or wherein R.sup.d and R.sup.e together with the
nitrogen to which they are bound form a morpholine ring, a
piperazine ring, or a 4-methyl-piperazine ring, --C(O)R.sup.f,
wherein R.sup.f is alkyl, --(CH.sub.2).sub.b-cycloalkyl,
--(CH.sub.2).sub.b--Oalkyl, --(CH.sub.2).sub.b-heterocycloalkyl,
wherein the heterocycloalkyl is selected from the group consisting
of morpholin-4-yl, tetrahydropyran-4-yl, 4-methyl-piperazin-1-yl,
4-isopropyl-piperazin-1-yl, piperazin-1-yl, thiomorpholin-4-yl,
4-hydroxy-4-methyl-piperidine-1-yl,
(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl,
(1R,5S)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl,
4-hydroxymethyl-piperidine-1-yl, 4-tert-butyl-piperazine-1-yl,
4-methyl-piperidine-1-yl, and piperidine-1-yl,
--O-heterocycloalkyl, wherein the heterocycloalkyl is
4-methyl-piperidine-1-yl, or piperidine-1-yl,
2-oxa-8-aza-spiro[4.5]decan-8-yl,
--(CH.sub.2).sub.b--NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, wherein cycloalkyl is selected from
cyclohexyl, 4-hydroxycyclohexyl, cyclopropyl,
2-phenyl-cycloprop-1-yl, or cyclopentyl,
--(CH.sub.2).sub.a--Oalkyl, --(CH.sub.2).sub.a--NR'R'', wherein R'
and R'' are each independently alkyl or cycloalkyl,
bicyclo[2.2.1]heptanyl, or --(CH.sub.2).sub.b-heterocycloalkyl,
wherein the heterocycloalkyl is 4-methyl-piperazin-1-yl,
tetrahydro-pyran-4-yl, 1-methyl-piperidin-4-yl,
1-benzyl-pyrrolidin-3-yl, 1,1-dioxo-tetrahydro-thiophen-3-yl,
morpholin-4-yl, piperidin-4-yl,
1-tert-butoxycarbonyl-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl,
1-isopropyl-piperidin-4-yl, 1-(2-methoxyethyl)-piperidin-4-yl,
1-(2-fluoroethyl)-piperidin-4-yl,
1-(3,3,3-trifluoropropyl)-piperidin-4-yl,
1-(2-methylsulfanyl-ethyl)-piperidin-4-yl,
3-(endo)-9-methyl-9-aza-bicyclo[3.3.1]non-3-yl,
1-(3,3,3-trifluoro-propionyl)-piperidin-4-yl,
1,1-dioxo-hexahydro-thiopyran-4-yl,
3-endo-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,
1-(2-fluoro-acetyl)-piperidin-4-yl, 1-methyl-pyrrolidin-3-yl,
1-methoxycarbonyl-piperidin-4-yl,
(3-exo)-8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(3-exo)-9-(2,2,2-trifluoro-ethyl)-9-aza-bicyclo[3.3.1]non-3-yl,
(3-exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(7-exo)-9-methyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl,
1-methyl-pyrrolidin-3-yl,
(3-exo)-9-cyclopropyl-9-aza-bicyclo[3.3.1]non-3-yl,
(7-exo)-9-methyl-3-thia-9-aza-bicyclo[3.3.1]non-7-yl,
1-cyanomethyl-piperidin-4-yl,
1-(2-methanesulfonyl-ethyl)-piperidin-4-yl,
(N,N-dimethylamino-carbonylmethylene)-piperidin-4-yl,
1-(2-hydroxy-ethyl)-piperidin-4-yl,
(3-exo)-9-isopropyl-9-aza-bicyclo[3.3.1]non-3-yl,
(3-exo)-8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(3-exo)-8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(1R,5S)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(1R,5S)-9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]non-3-yl, or
1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl, --C(S)NH.sub.2,
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or tetrahydro-2H-pyran-4-yl,
--S(O).sub.2-heterocycloalkyl, wherein the heterocycloalkyl is
selected from the group consisting of pyrrolidin-1-yl,
3,3-difluoro-pyrrolidin-1-yl, morpholin-4-yl,
4-methyl-piperazin-1-yl, piperazin-1-yl, thiomorpholin-4-yl,
1,1-dioxo-thiomorpholin-4-yl, 4-methoxymethyl-piperidin-1-yl,
4-methoxy-piperidine-1-yl,
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl,
(1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl, or
--S(O).sub.2-spirocyclic heteroalkyl, wherein the spirocyclic
heteroalkyl is 2-oxa-8-aza-spiro[4.5]decan-8-yl, or
1,4-dioxa-8-aza-spiro[4.5]decanyl, a is 1 to 6, and b is 0 to
6.
11. The compound of claim 1, wherein R.sup.2 is --C(O)R.sup.f,
wherein R.sup.f is --(CH.sub.2).sub.b-cycloalkyl,
--(CH.sub.2).sub.b-heterocycloalkyl, or
--(CH.sub.2).sub.b-NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.a--Oalkyl, bicyclic
cycloalkyl, bicyclic cycloalkenyl,
--(CH.sub.2).sub.b-heterocycloalkyl, or --(CH.sub.2).sub.a--NR'R'',
wherein R' and R'' are each independently hydrogen, alkyl or
cycloalkyl, --S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and
R.sup.viii are each independently H, alkyl, --C(O)Oalkyl,
alkylene-O alkyl, cycloalkyl, or heterocycloalkyl, or
--S(O).sub.2-heterocycloalkyl, a is 1 to 6, preferably 1 to 4, more
preferably 2, b is 0 to 6, preferably 0 to 4, more preferably 0 or
1, heterocycloalkyl is unsubstituted or substituted with one or
more substituents independently selected from the group consisting
of alkyl, hydroxy, hydroxyalkyl, benzyl, oxo, --C(O)Oalkyl,
cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl, cyanoalkyl,
alkylene-S(O).sub.2-alkyl, -alkylene-C(O)N(alkyl).sub.2, halo,
haloalkyl and alkyoxy; and cycloalkyl is unsubstituted or
substituted with one or more substituents independently selected
from the group consisting of alkyl, hydroxy, hydroxyalkyl, phenyl,
oxo, cyanoalkyl, -alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl,
haloalkyl, halo, and alkyoxy.
12. The compound of claim 1, wherein A is --CH.sub.2-- and n is 1
or 2 or wherein A is --O-- and n is 1.
13. The compound of claim 12, wherein A is --CH.sub.2-- and n is
1.
14. The compound of claim 12, wherein A is --CH.sub.2-- and n is
2.
15. The compound of claim 12, wherein A is --O-- and n is 1.
16. The compound of claim 1, wherein R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are each indepentenly selected from the group consisting of
H, halo, alkoxy, alkyl, haloalkoxy, or --O-alkylene-O-alkyl.
17. The compound of claim 16, wherein R.sup.3 is H, halo, or
alkyl.
18. The compound of claim 17, wherein R.sup.3 is H, chloro, or
methyl.
19. The compound of claim 16, wherein R.sup.4 is H, halo, or
alkyl.
20. The compound of claim 19, wherein R.sup.4 is H, fluor, or
methyl.
21. The compound of claim 16, wherein R.sup.5is H or halo.
22. The compound of claim 21, wherein R.sup.5is H, fluoro, or
chloro.
23. The compound of claim 16, wherein R.sup.6 is H, alkoxy, alkyl,
halo, or --O-alkylene-O-alkyl.
24. The compound of claim 23, wherein R.sup.6 is H, halo,
C.sub.1-4alkoxy, C.sub.1-4alkyl, fluoro, or
--O--CH.sub.2CH.sub.2OMe.
25. The compound of claim 16, wherein R.sup.3, R.sup.4, R.sup.5,
and R.sup.6 all are H.
26. The compound of claim 16, wherein R.sup.3, R.sup.4, and R.sup.5
are H and R.sup.6 is alkoxy, alkyl, halo, or
--O-alkylene-O-alkyl.
27. The compound of claim 16, wherein R.sup.3, R.sup.5, and R.sup.6
are H and R.sup.4 is halo.
28. The compound of claim 16, wherein R.sup.3, R.sup.4, and R.sup.6
are H and R.sup.5is halo.
29. The compound of claim 16, wherein R.sup.3 and R.sup.5 are
chloro, R.sup.4 is H, and R.sup.6is methoxy.
30. The compound of claim 16, wherein R.sup.3is alkyl, R.sup.4 and
R.sup.5 are H, and R.sup.6 is alkoxy.
31. The compound of claim 16, wherein R.sup.3 and R.sup.5 are H,
R.sup.4 is alkyl, and R.sup.6is alkoxy.
32. The compound of claim 1 wherein not all of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are simultaneously H.
33. The compound of claim 1, selected from the group consisting of
N.sup.6-(3-Dimethylamino-propyl)-N.sup.2--(R)-indan-1-yl-quinoline-2,6-di-
amine; (R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea;
N.sup.6-Allyl-N.sup.2--(R)-indan-1-yl-quinoline-2,6-diamine;
1-Cyclohexyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((1S,2R)-2-phenyl-cyclopropyl-
)-urea; 1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-methyl-urea;
1-tert-Butyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea;
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-urea; and
rac-1-[2-(2,3-Dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-isopropyl-ur-
ea.
34. The compound of claim 1, selected from the group consisting of
(+)-1-{2-[-(2,3-Dihydro-benzofuran-3-yl)amino]-quinolin-6-yl}-3-isopropyl-
-urea;
rac-1-Isopropyl-3-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-ure-
a;
(-)-1-Isopropyl-3-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-urea;
rac-N.sup.2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; rac-1-Isopropyl-3-[2-(8-methoxy-1,2,3
,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-urea;
4-Methyl-piperazine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(2-methoxy-ethyl)-urea;
1-(2-Dimethylamino-ethyl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(tetrahydro-pyran-4-yl)-urea;
and
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-piperidin-4-yl)-
-urea.
35. The compound of claim 1, selected from the group consisting of
1-Cyclopropyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea;
Morpholine-4-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
1-Cyclopropylmethyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea;
Thiomorpholine-4-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
1-(1-Benzyl-pyrrolidin-3-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-ur-
ea;
1-Bicyclo[2.2.1]hept-2-yl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-ur-
ea;
1-(1,1-Dioxo-tetrahydro-thiophen-3-yl)-3-[2-((R)-indan-1-ylamino)-quin-
olin-6-yl]-urea;
1-Ethyl-1-(4-hydroxy-cyclohexyl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl-
]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(2-morpholin-4-yl-ethy-
l)-urea; and 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide.
36. The compound of claim 1, selected from the group consisting of
2-Oxa-8-aza-spiro[4.5]decane-8-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
1-[2-(Cyclopropyl-methyl-amino)-ethyl]-3-[2-((R)-indan-1-ylamino)-quinoli-
n-6-yl]-urea;
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide; (1R,5
S)-8-Oxa-3-aza-bicyclo[3.2.1]octane-3-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
rac-1-[2-(2,3-Dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-(1-methyl-pi-
peridin-4-yl)-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[2-(tetrahydro-pyran-2-yloxy)-
-ethyl]-urea; 4-Hydroxymethyl-piperidine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidine-1-carboxy-
lic acid tert-butyl ester;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea;
and
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-piperidin-
-4-yl)-urea.
37. The compound of claim 1, selected from the group consisting of
1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl-
]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperidin-
-4-yl)-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methoxy-ethyl)-piperidi-
n-4-yl]-urea;
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-quino-
lin-6-yl]-urea;
rac-1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamin-
o)-quinolin-6-yl]-urea;
rac-1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamino-
)-quinolin-6-yl]-urea;
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-
-propyl)-piperidin-4-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methylsulfanyl-ethyl)-p-
iperidin-4-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((endo)-9-methyl-9-aza-bicycl-
o[3.3.1]non-3-yl)-urea; and
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-(9-methyl-9-aza-bicyc-
lo[3.3.1]non-3-yl)-urea.
38. The compound of claim 1, selected from the group consisting of
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methylsulfany-
l-ethyl)-piperidin-4-yl]-urea;
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-
-propionyl)-piperidin-4-yl]-urea;
rac-1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-qui-
nolin-6-yl]-urea;
rac-1-(1,1-Dioxo-hexahydro-thiopyran-4-yl)-3-[2-(8-methoxy-1,2,3,4-tetrah-
ydro-naphthalen-1-ylamino)-quinolin-6-yl]-urea;
rac-1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-(8-methoxy-1,2,3,4-tetrahydro-n-
aphthalen-1-ylamino)-quinolin-6-yl]-urea;
rac-1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-y-
l]-3-endo-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-urea;
rac-1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-y-
l]-3-(1-methyl-piperidin-4-yl)-urea;
rac-1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-3-[2-(8-methoxy-1,2,3,4-tetrah-
ydro-naphthalen-1-ylamino)-quinolin-6-yl]-urea;
rac-1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-(8-methoxy-1,2,3,4-tetrahy-
dro-naphthalen-1-ylamino)-quinolin-6-yl]-urea; and
rac-endo-1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinoli-
n-6-yl]-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-urea.
39. The compound of claim 1, selected from the group consisting of
1-[1-(2-Fluoro-acetyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinoli-
n-6-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-propionyl-
)-piperidin-4-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-propyl)-p-
iperidin-4-yl]-urea;
1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-3-
-((S)-1-methyl-pyrrolidin-3-yl)-urea;
rac-1-[2-(4,6-Dichloro-7-methoxy-indan-1-ylamino)-quinolin-6-yl]-3-isopro-
pyl-urea;
N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N,N-di-
methylsulfamide;
rac-N'-[2-(2,3-dihydro-1-benzofuran-3-ylamino)quinolin-6-yl]-N,N-dimethyl-
sulfamide;
rac-N'-{2-[(7-methoxy-2,3-dihydro-1H-inden-1-yl)amino]quinolin--
6-yl}-N,N-dimethylsulfamide;
rac-N'-{2-[(8-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)amino]quinolin-6--
yl}-N,N-dimethylsulfamide; and
rac-N'-{2-[(4,6-Dichloro-7-methoxy-2,3-dihydro-1H-inden-1-yl)amino]quinol-
in-6-yl}-N,N-dimethylsulfamide.
40. The compound of claim 1, selected from the group consisting of
tert-butyl
[({2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}amino)sulfonyl]ca-
rbamate;
N-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}sulfamide
hydrochloride; Pyrrolidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
3,3-Difluoro-pyrrolidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
(2-Methoxy-ethyl)-methyl-sulfonic acid
[2-((R)-indan-1-ylamino)quinolin-6-yl]-amide; Morpholine-4-sulfonic
acid [2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
4-Methyl-piperazine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
Thiomorpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
1,1-Dioxo-thiomorpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide; and
N-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N'-(tetrahydro-2-
H-pyran-4-yl)sulfamide.
41. The compound of claim 1, selected from the group consisting of
N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N-methyl-N-(tet-
rahydro-2H-pyran-4-yl)sulfamide;
1,4-Dioxa-8-aza-spiro[4.5]decane-8-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
4-Methoxymethyl-piperidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
4-Methoxy-piperidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
N-cyclopropyl-N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N-
-methylsulfamide;
N-(cyclopropylmethyl)-N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-
-6-yl}-N-methylsulfamide; 2-Oxa-8-aza-spiro[4.5]decane-8-sulfonic
acid [2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
(1S,5R)-8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-yl]-amide; and
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-amide.
42. The compound of claim 1, selected from the group consisting of
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-ami-
de;
N-Cyclopropyl-N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl-
}sulfamide;
rac-1-Isopropyl-3-[2-(7-methoxy-4-methyl-indan-1-ylamino)-quinolin-6-yl]--
urea;
rac-N'-{2-[(7-Methoxy-4-methyl-2,3-dihydro-1H-inden-1-yl)amino]quino-
lin-6-yl}-N,N-dimethylsulfamide;
rac-1-[2-(7-Methoxy-4-methyl-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl--
piperidin-4-yl)-urea;
4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidine-1-carboxy-
lic acid methyl ester;
1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinolin-
-6-yl]-urea;
rac-1-[2-(4,6-dichloro-7-methoxy-indan-1-ylamino)-quinolin-6-yl]-3-(1-met-
hyl-piperidin-4-yl)-urea;
1-((3-exo)-8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-((R)-indan-1--
ylamino)-quinolin-6-yl]-urea; and
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[(3-exo)-9-(2,2,2-trifluoro-e-
thyl)-9-aza-bicyclo[3.3.1]non-3-yl]-urea.
43. The compound of claim 1, selected from the group consisting of
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-8-methyl-8-aza-bicyc-
lo[3.2.1]oct-3-yl)-urea;
rac-N.sup.2-(7-Methyl-indan-1-yl)-quinoline-2,6-diamine;
rac-1-Isopropyl-3-[2-(7-methyl-indan-1-ylamino)-quinolin-6-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((7-exo)-9-methyl-3-oxa-9-aza-
-bicyclo[3.3.1]non-7-yl)-urea;
1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-3-
-((R)-1-methyl-pyrrolidin-3-yl)-urea;
rac-N.sup.2-(5-Fluoro-indan-1-yl)-quinoline-2,6-diamine;
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea;
{2-[2-((R)-Indan-1-ylamino)-quinolin-6-ylamino]-ethyl}-methyl-carbamic
acid tert-butyl ester;
N.sup.2--(R)-Indan-1-yl-N-6-(2-methylamino-ethyl)-quinoline-2,6-diamine;
and
1-((3-exo)-9-Cyclopropyl-9-aza-bicyclo[3.3.1]non-3-yl)-3-[2-((R)-inda-
n-1-ylamino)-quinolin-6-yl]-urea.
44. The compound of claim 1, selected from the group consisting of
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((7-exo)-9-methyl-3-thia-9-az-
a-bicyclo[3.3.1]non-7-yl)-urea; 4-Isopropyl-piperazine-1-carboxylic
acid [2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
4-tert-Butyl-piperazine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-methyl-imidazolidin-2-one;
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperid-
in-4-yl)-urea;
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-isobutyramide;
2-Cyclopentyl-N-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-acetamide;
rac-N-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-y-
l]-isobutyramide;
rac-2-Dimethylamino-N-[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylami-
no)-quinolin-6-yl]-acetamide; and
rac-2-Methoxy-N-[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-qu-
inolin-6-yl]-acetamide.
45. The compound of claim 1, selected from the group consisting of
rac-N-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-y-
l]-2-morpholin-4-yl-acetamide;
{[2-((R)-Indan-1-ylamino)-quinolin-6-ylcarbamoyl]-methyl}-arbamic
acid tert-butyl ester;
2-Amino-N-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-acetamide;
1-Methyl-piperidine-4-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide;
rac-N-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-y-
l]-2-(tetrahydro-pyran-4-yl)-acetamide;
rac-2-Dimethylamino-N-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-aceta-
mide;
rac-N-[2-(6-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piper-
azin-1-yl)-acetamide;
rac-(N)-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-isobutyramide;
rac-1-Methyl-piperidine-4-carboxylic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide; and
rac-1-Isopropyl-3-[2-(7-methoxy-5-methyl-indan-1-ylamino)-quinolin-6-yl]--
urea.
46. The compound of claim 1, selected from the group consisting of
rac-1-[2-(7-Methoxy-5-methyl-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl--
piperidin-4-yl)-urea;
rac-N'-{2-[(7-Methoxy-5-methyl-2,3-dihydro-1H-inden-1-yl)amino]quinolin-6-
-yl}-N,N-dimethylsulfamide;
1-(1-Cyanomethyl-piperidin-4-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl-
]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2,2,2-trifluoro-et-
hyl)-piperidin-4-yl]-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methanesulfonyl-ethyl)--
piperidin-4-yl]-urea;
2-(4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidin-1-yl)-N-
,N-dimethyl-acetamide;
1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinoli-
n-6-yl]-urea; [2-((R)-Indan-1-ylamino)-quinolin-6-yl]-carbamic acid
isopropyl ester;
rac-N-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-
-1-yl)-acetamide; and rac-Cyclopropanecarboxylic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide.
47. The compound of claim 1, selected from the group consisting of
rac-Cyclopropanecarboxylic acid
[2-(5-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide;
rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin--
1-yl)-acetamide;
rac-N.sup.2-(6-Fluoro-indan-1-yl)-quinoline-2,6-diamine;
rac-1-[2-(6-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea;
rac-N.sup.2-(7-Fluoro-indan-1-yl)-quinoline-2,6-diamine;
rac-1-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea;
rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-isopropyl-piperaz-
in-1-yl)-acetamide;
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide;
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-thiourea; and
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea
hydroiodide.
48. The compound of claim 1, selected from the group consisting of
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-morpholine-4-carboxamidine;
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-N'-(
1-methyl-piperidin-4-yl)-guanidine;
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-N-isopropyl-guanidine;
N-Cyclopropyl-N'-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-guanidine;
rac-1-[2-(6-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperid-
in-4-yl)-urea;
rac-1-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperid-
in-4-yl)-urea;
rac-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-carbamic acid
methyl ester;
rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-morpholin-4-yl-aceta-
mide; rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-acetamide;
rac-2-Cyclopropyl-N-[2-(5-fluoro-indan-1-ylamino)-quinolin-6-yl]-acetamid-
e.
49. The compound of claim 1, selected from the group consisting of
rac-N-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin--
1-yl)-acetamide; rac-Cyclopropanecarboxylic acid
[2-(7-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide;
N.sup.2--(R)-Indan-1-yl-N6-morpholin-4-yl-quinoline-2,6-diamine;
N.sup.2--(R)-Indan-1-yl-N6-(4-methyl-piperazin-1-yl)-quinoline-2,6-diamin-
e;
(R)-Indan-1-yl-[6-(4-methyl-piperazin-1-yl)-quinolin-2-yl]-amine;
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-N',N''-diisopropyl-guanidine;
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-carbamic acid
1-methyl-piperidin-4-yl ester;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-9-isopropyl-9-aza-bi-
cyclo[3.3.1]non-3-yl)-urea;
1-((3-exo)-8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-((R)-indan-1--
ylamino)-quinolin-6-yl]-1-methyl-urea; and
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-8-isopropyl-8-aza-bi-
cyclo[3.2.1]oct-3-yl)-urea.
50. The compound of claim 1, selected from the group consisting of
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-carbamic acid methyl ester;
rac-N.sup.2-(7-Methoxy-indan-1-yl)-quinoline-2,6-diamine;
rac-N.sup.2-(4-Methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine-
;
rac-N.sup.2-[4-(2-Methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-quinoline-
-2,6-diamine;
rac-N.sup.2-(4-Ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine;
3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-1-(1-isopropyl-piperidin-4-yl)--
1-methyl-urea;
3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-1-methyl-1-((3-exo)-8-methyl-8--
aza-bicyclo[3.2.1]oct-3-yl)-urea;
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((7-exo)-9-isopropyl-3-oxa-9--
aza-bicyclo[3.3.1]non-7-yl)-urea;
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-quino-
lin-6-yl]-1-methyl-urea;
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benzofuran-
-3-ylamino)-quinolin-6-yl]-urea; and
rac-1-[2-(4-Ethoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-(1--
isopropyl-piperidin-4-yl)-urea.
51. The compound of claim 1, selected from the group consisting of
rac-1-(1-Isopropyl-piperidin-4-yl)-3-{2-[4-(2-methoxy-ethoxy)-2,3-dihydro-
-benzofuran-3-ylamino]-quinolin-6-yl}-urea;
rac-N-[2-(4-Methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-2-(4-
-methyl-piperazin-1-yl)-acetamide;
rac-N-[2-(4-Ethoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-2-(4--
methyl-piperazin-1-yl)-acetamide;
rac-N-{2-[4-(2-Methoxy-ethoxy)-2,3-dihydro-benzofuran-3-ylamino]-quinolin-
-6-yl}-2-(4-methyl-piperazin-1-yl)-acetamide;
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(7-methoxy--
indan-1-ylamino)-quinolin-6-yl]-urea;
rac-3-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-1-(1-isopropyl-piperid-
in-4-yl)-1-methyl-urea;
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(7-methoxy--
indan-1-ylamino)-quinolin-6-yl]-1-methyl-urea;
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamin-
o)-quinolin-6-yl]-urea; rac-Cyclopropanecarboxylic acid
[2-(6-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide;
rac-1-[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-3-[2-(7-methoxy-inda-
n-1-ylamino)-quinolin-6-yl]-1-methyl-urea; and
1-[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamin-
o)-quinolin-6-yl]-1-methyl-urea.
52. The compound of claim 1, selected from the group consisting of
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benzofuran-
-3-ylamino)-quinolin-6-yl]-1-methyl-urea;
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(4-methoxy--
2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-methyl-urea;
rac-Cyclopropanecarboxylic acid
[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-amide;
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-acetamide;
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-hydroxy-ethyl)-
-piperidin-4-yl]-urea;
(-)-N-[2-((S)-4-Methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]--
2-(4-methyl-piperazin-1-yl)-acetamide;
rac-1-[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-3-[2-(4-methoxy-2,3--
dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-methyl-urea;
rac-N-2-(6-Fluoro-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine;
rac-N-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-methoxy-acetamide;
rac-3-[2-(6-Fluoro-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-(1--
isopropyl-piperidin-4-yl)-1-methyl-urea; and
rac-N-[2-(6-Fluoro-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-2-(4--
methyl-piperazin-1-yl)-acetamide.
53. The compound of claim 1, selected from the group consisting of
(-)-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benzofuran-
-3-ylamino)-quinolin-6-yl]-1-methyl-urea;
1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinoli-
n-6-yl]-1-methyl-urea;
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamin-
o)-quinolin-6-yl]-1-methyl-urea;
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(4-methoxy-2,3-dihydro-be-
nzofuran-3-ylamino)-quinolin-6-yl]-1-methyl-urea;
rac-3-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-1-[1-(2-hydroxy-ethyl)-
-piperidin-4-yl]-1-methyl-urea;
rac-3-[2-(6-Fluoro-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-[1--
(2-hydroxy-ethyl)-piperidin-4-yl]-1-methyl-urea;
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-1-yl)-ace-
tamide;
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2,2-dimethyl-propionamid-
e;
rac-N-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-2-morpholin-4-yl-ac-
etamide;
rac-2-(2-Dimethylamino-ethylamino)-N-[2-(7-methoxy-indan-1-ylamin-
o)-quinolin-6-yl]-acetamide; and
rac-2-(4-Cyclopropyl-piperazin-1-yl)-N-[2-(7-methoxy-indan-1-ylamino)-qui-
nolin-6-yl]-acetamide.
54. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula (I) ##STR00026## wherein
A is --CH.sub.2-- or --O--; R.sup.1 is hydrogen or alkyl; R.sup.2
is hydrogen, heterocycloalkyl, --(CH.sub.2).sub.a--R.sup.a, wherein
R.sup.a is hydrogen, alkoxy, hydroxy, cyano, or NR.sup.iR.sup.ii,
wherein R.sup.i and R.sup.ii are each independently hydrogen, alkyl
or C(O)O-alkyl, allyl, --C(NH)--S--R.sup.b, wherein R.sup.b is
alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, or alkenyl,
--C(NR.sup.c)NR.sup.dR.sup.e, wherein R.sup.c, R.sup.d, and R.sup.e
are each independently hydrogen, alkyl, cycloalkyl,
heterocycloalkyl, or wherein R.sup.d and R.sup.e together with the
nitrogen to which they are bound form a heterocycloalkyl,
--C(O)R.sup.f, wherein R.sup.f is alkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.b--Oalkyl,
--(CH.sub.2).sub.b-heterocycloalkyl, --O-heterocycloalkyl, or
--(CH.sub.2).sub.b--NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.a--Oalkyl, bicyclic
cycloalkyl, bicyclic cycloalkenyl,
--(CH.sub.2).sub.b-heterocycloalkyl,
--(CH.sub.2).sub.a--O-heterocycloalkyl, or
--(CH.sub.2).sub.a--NR'R'', wherein R' and R'' are each
independently hydrogen, alkyl or cycloalkyl,
--C(S)NR.sup.vR.sup.vi, wherein R.sup.v and R.sup.vi are each
independently H, alkyl or cycloalkyl,
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or heterocycloalkyl, or --S(O).sub.2-heterocycloalkyl,
or R.sup.1 and R.sup.2 together with the N atom to which they are
bound form a 5- or 6-membered heterocycloalkyl; R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are each indepentenly selected from from the
group consisting of H, halo, alkyl, haloalkyl, hydroxyalkyl,
cyanoalkyl, alkoxy, haloalkoxy, --O-alkylene-O-alkyl, hydroxyl,
oxo, cyano, nitro and NR.sup.ixR.sup.x, wherein R.sup.ix and
R.sup.x are each independently H or alkyl; a is 1 to 6; b is 0 to
6; and n is 1 or 2, and wherein heterocycloalkyl is unsubstituted
or substituted with one or more substituents independently selected
from the group consisting of alkyl, hydroxy, hydroxyalkyl, benzyl,
oxo, --C(O)Oalkyl, cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl,
cyanoalkyl, alkylene-S(O).sub.2-alkyl,
-alkylene-C(O)N(alkyl).sub.2, halo, haloalkyl and alkyoxy; and
wherein cycloalkyl is unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
alkyl, hydroxy, hydroxyalkyl, phenyl, oxo,
cyanoalkyl,-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl,
halo, and alkyoxy; or a pharmaceutically acceptable salt thereof
and a pharmaceutically acceptable carrier.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 08152327.6, filed Mar. 5, 2008, which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin)
modulates a wide range of physiological and pathological processes
in the central nervous system and periphery, including anxiety,
sleep regulation, aggression, feeding and depression (Hoyer et al.,
Pharmacol. Rev. 46, 157-204, 1994). Both pharmacological
characterization and molecular cloning of several 5-HT receptor
genes has revealed that 5-HT mediates its diverse physiological
actions through a multiplicity of receptor subtypes. These
receptors belong to at least two different protein superfamilies:
ligand-gated ion channel receptor (5-HT.sub.3) and the
G-protein-coupled 7-transmembrane receptors (thirteen distinct
receptors cloned to date). In addition, within the
G-protein-coupled receptors, serotonin exerts its actions through a
multiplicity of signal transduction mechanisms.
[0003] The cloning and characterization of the human 5-HT.sub.5A
serotonin receptor has been described in FEBS Letters, 355, 242-246
(1994). The sequence is not closely related to that of any
previously known serotonin receptor, with the best homology being
35% to the human 5-HT.sub.1B receptor. It encodes a predicted 357
amino-acid protein, with seven putative transmembrane domains,
consistent with that of a G-protein coupled receptor. The sequence
is characterized by containing an intron between transmembrane
domains V and VI. More recently coupling to Gi/o .alpha. mechanisms
has been demonstrated with the inhibition of forskolin stimulated
cAMP and also evidence for more complicated G-protein mediated
coupling mechanisms have been proposed (Francken et al. Eur. J.
Pharmacol. 361, 299-309, 1998; Noda et al., J. Neurochem. 84,
222-232, 2003). Furthermore, in WO 2004/096771 it is described the
use of compounds, which are active on the 5-HT.sub.5A serotonin
receptor for the treatment of depression, anxiety disorders,
schizophrenia, panic disorders, agoraphobia, social phobia,
obsessive compulsive disorders, post-traumatic stress disorders,
pain, memory disorders, dementia, disorders of eating behaviors,
sexual dysfunction, sleep disorders, withdrawal from abuse of
drugs, motor disorders such as Parkinson's disease, psychiatric
disorders or gastrointestinal disorders.
[0004] The Pharmacology & Therapeutics, 111, 707-714 (2006)
describes potential therapeutic utility of 5-HT.sub.5A receptor
ligands for the treatment of circadian rhythm, sleep disturbances,
mood disorders, schizophrenia, cognitive disorders and autism. The
Journal of Comparative Neurology, 476, 316-329 (2004) suggests
based on the localisation pattern of the 5-HT.sub.5A receptor in
the rat spinal cord that 5-HT.sub.5A receptors may play a role in
central motor control, nociception and autonomic function such as
stress induced urinary incontinence and overactive bladder.
[0005] The Journal of Psychiatric Research, 38, 371-376 (2004)
describes evidence for a potential significant role of the
5-HT.sub.5A gene in schizophrenia and more specifically in patients
with later age at onset.
SUMMARY OF THE INVENTION
[0006] The present invention provides 2-aminoquinoline derivatives.
In particular, the present invention provides compounds of formula
(I)
##STR00002##
wherein [0007] A is --CH.sub.2-- or --O--; [0008] R.sup.1 is
hydrogen or alkyl; [0009] R.sup.2 is hydrogen, [0010]
heterocycloalkyl, [0011] --(CH.sub.2).sub.a--R.sup.a, wherein
R.sup.a is hydrogen, alkoxy, hydroxy, cyano, or NR.sup.iR.sup.ii,
wherein R.sup.i and R.sup.ii are each independently hydrogen, alkyl
or C(O)O-alkyl, [0012] allyl, [0013] --C(NH)--S--R.sup.b, wherein
R.sup.b is alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl,
or alkenyl, [0014] --C(NR.sup.c)NR.sup.dR.sup.e, wherein R.sup.c,
R.sup.d, and R.sup.e are each independently hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, or wherein R.sup.d and R.sup.e
together with the nitrogen to which they are bound form a
heterocycloalkyl, [0015] --C(O)R.sup.f, wherein R.sup.f is alkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.b--Oalkyl,
--(CH.sub.2).sub.b-heterocycloalkyl, --O-heterocycloalkyl, or
--(CH.sub.2).sub.b--NR.sup.iiiR.sup.iv, [0016] wherein R.sup.iii
and R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.a--Oalkyl, bicyclic
cycloalkyl, bicyclic cycloalkenyl,
--(CH.sub.2).sub.b-heterocycloalkyl,
--(CH.sub.2).sub.a--O-heterocycloalkyl, or
--(CH.sub.2).sub.a--NR'R'', wherein R' and R'' are each
independently hydrogen, alkyl or cycloalkyl, [0017]
--C(S)NR.sup.vR.sup.vi, wherein R.sup.v and R.sup.vi are each
independently H, alkyl or cycloalkyl, [0018]
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or heterocycloalkyl, [0019]
--S(O).sub.2-heterocycloalkyl, or [0020] R.sup.1 and R.sup.2
together with the N atom to which they are bound form a 5- or
6-membered heterocycloalkyl, [0021] R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are each independently selected from the group consisting
of H, halo, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy,
haloalkoxy, --O-alkylene-O-alkyl, hydroxyl, oxo, cyano, nitro and
NR.sup.ixR.sup.x, wherein R.sup.ix and R.sup.x are each
independently H or alkyl; [0022] a is 1 to 6; [0023] b is 0 to 6;
and [0024] n is 1 or 2, and wherein [0025] heterocycloalkyl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, hydroxy,
hydroxyalkyl, benzyl, oxo, --C(O)Oalkyl, cycloalkyl,
alkylene-O-alkyl, --C(O)haloalkyl, cyanoalkyl,
alkylene-S(O).sub.2-alkyl, -alkylene-C(O)N(alkyl).sub.2, halo,
haloalkyl and alkyoxy; and wherein [0026] cycloalkyl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, hydroxy,
hydroxyalkyl, phenyl, oxo, cyanoalkyl,
-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl, halo, AND
alkyoxy; [0027] or a pharmaceutically acceptable salt thereof.
[0028] The compounds of formula I can contain asymmetric carbon
atoms. Accordingly, the present invention includes all
stereoisomeric forms of the compounds of formula I, including each
of the individual enantiomers and mixtures thereof, i.e. their
individual optical isomers and mixtures thereof.
[0029] The present invention also includes pharmaceutical
compositions containing a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable salt there
of and a pharmaceutically acceptable carrier. The invention also
provides methods for the manufacture of the compounds and
compositions of the invention.
[0030] Compounds of formula I have good activity on the 5-HT.sub.5A
receptor. Therefore, the invention provides methods for the
treatment of depression (which term includes bipolar depression,
unipolar depression, single or recurrent major depressive episodes
with or without psychotic features, catatonic features, melancholic
features, atypical features or postpartum onset, seasonal affective
disorders and dysthymia, depressive disorders resulting from a
general medical condition including, but not limited to, myocardial
infarction, diabetes, miscarriage or abortion), anxiety disorders,
(which includes generalized anxiety and social anxiety disorder,
panic disorders, agoraphobia, social phobia, obsessive compulsive
disorders, post-traumatic stress disorders), psychotic disorders
(which includes schizophrenia, schizoaffective disorders, bipolar
disease, mania, psychotic depression, and other psychoses involving
paranoia and delusions), pain (particularly neuropathic pain),
memory disorders (including dementia, amnesic disorders and
age-associated memory impairment), disorders of eating behaviors
(including nervosa and bulimia nervosa), sexual dysfunction, sleep
disorders (including disturbances of circadian rhythm, dyssomnia,
insomnia, sleep apnea and narcolepsy), withdrawal from abuse of
drugs (such as of cocaine, nicotine, benzodiazepines, alcohol
(ethanol), caffeine, phencyclidine and phencyclidine-like
compounds, opiates such as cannabis, heroin, morphine, sedative
hypnotic, amphetamine or amphetamine-related drugs), motor
disorders such as Parkinson's disease, dementia in Parkinson's
disease, neuroleptic-induced Parkinsonism and tardive dyskinesias,
as well as other psychiatric disorders and gastrointestinal
disorders such as irritable bowel syndrome (WO 2004/096771).
[0031] The preferred indications with regard to the present
invention are the treatment of anxiety, depression, sleep disorders
and schizophrenia.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The following definitions of general terms used herein apply
irrespective of whether the terms in question appear alone or in
combination. It must be noted that, as used in the specification
and the appended claims, the singular forms "a", "an," and "the"
include plural forms unless the context clearly dictates
otherwise.
[0033] As used herein, the term "allyl" denotes a group
--CH.sub.2CH.dbd.CH.sub.2.
[0034] As used herein, the term "alkyl" denotes monovalent linear
or branched saturated hydrocarbon moiety, consisting solely of
carbon and hydrogen atoms, having from 1 to 7 carbon atoms, for
example, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl,
sec-butyl, tert-butyl and the like. Preferred alkyl groups are
groups with 1, 2, 3 or 4 carbon atoms.
[0035] As used herein, the term "alkylene" means a linear saturated
divalent hydrocarbon radical of one to seven carbon atoms or a
branched saturated divalent hydrocarbon radical of three to seven
carbon atoms. Preferred are divalent hydrocarbon radicals of one to
four carbon atoms.
[0036] The term "halo" denotes chloro, iodo, fluoro and bromo.
Preferred halo are fluoro, chloro and bromo, more preferred are
fluoro and chloro.
[0037] The term "haloalkyl" denotes an alkyl group as defined above
wherein at least one of the hydrogen atoms of the alkyl group is
replaced by a halogen atom, preferably fluoro or chloro, most
preferably fluoro. Examples of haloalkyl include but are not
limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl,
tert-butyl, pentyl or n-hexyl substituted by one or more Cl, F, Br
or I atom(s) as well as those groups specifically illustrated by
the examples herein below. Among the preferred haloalkyl groups are
monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for
example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
fluoromethyl, trifluoromethyl.
[0038] The term "hydroxyalkyl" denotes an alkyl group as defined
above wherein at least one of the hydrogen atoms of the alkyl group
is replaced by a hydroxy group. Examples of hydroxyalkyl include
but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more
OH, as well as those groups specifically illustrated by the
examples herein below.
[0039] The term "cyanoyalkyl" denotes an alkyl group as defined
above wherein at least one of the hydrogen atoms of the alkyl group
is replaced by a cyano group. Examples of cyanoalkyl include but
are not limited to methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more
CN, as well as those groups specifically illustrated by the
examples herein below.
[0040] The term "alkoxy" denotes a group --O--R' wherein R' is
alkyl as defined above.
[0041] The term "aromatic" means the presence of an electron sextet
in a ring, according to Huckel's rule.
[0042] The term "cycloalkyl" refers to a monovalent saturated
monocyclic hydrocarbon radical of 3 to 7 ring carbon atoms, such as
cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.
Preferred are cyclopropyl, cyclopentyl and cyclohexyl. Cycloalkyl
is optionally substituted as described herein.
[0043] The term "bicyclic cycloalkyl" denotes a monovalent
saturated bicyclic hydrocarbon radical of 7 or 8 ring carbon atoms.
Bicyclic means consisting of two saturated carbocycles having two
carbon atoms in common, i.e. the bridge separating the two rings is
either a single bond or a chain of preferably one or two carbon
atoms. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl,
and bicyclo[2.2.2]octanyl. Corresponding "bicyclic cycloalkenyl"
preferably bear one double bond in their ring system, examples are
bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2]octenyl. Bicyclic
cycloalkyl or cycloalkenyl is optionally substituted as described
herein. Examples for substituents are independently selected from
alkyl, hydroxy, hydroxyalkyl, phenyl, oxo,
cyanoalkyl,-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl,
halo, or alkyoxy. Preferred substituents are halo, hydroxy, and
phenyl.
[0044] The term "heterocycloalkyl" refers to a monovalent saturated
5- to 11-membered monocyclic, bicyclic or spirocyclic ring system
containing one, two or three ring heteroatoms selected from N, O
and S, the remaining ring atoms being carbon atoms. In case of
monocyclic heterocycloalkyl, the ring is preferably 5- or
6-membered, in case of bicyclic heterocycloalkyl, the bicyclic ring
is preferably 7-, 8- or 9-membered and in case of spirocyclic
heterocycloalkyl, the ring system is preferably 10- or 11-membered.
"Heterocycloalkyl" may be unsubstituted or substituted as described
herein. Examples for substituents on heterocycloalkyl are
independently selected from alkyl, hydroxy, hydroxyalkyl, benzyl,
oxo, --C(O)Oalkyl, cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl,
cyanoalkyl, alkylene-S(O).sub.2-alkyl,
-alkylene-C(O)N(alkyl).sub.2, halo, haloalkyl and alkyoxy.
[0045] The term "5- or 6-membered heterocycloalkyl" refers to a
monovalent saturated monocycle as defined above. Preferably, 5- or
6-membered heterocloalkyl is a monovalent saturated monocyclic ring
containing one or two ring heteroatoms selected from N, O, and S.
Examples for 5- or 6-membered heterocycloclakyl moieties are
tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,
tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, morpholinyl,
thiomorpholinyl, piperidinyl, and piperazinyl. The 5- or 6-membered
heterocycloalkyl moiety is optionally substituted as described
herein.
[0046] The term "7-, 8- or 9-membered bicyclic heterocycloalkyl"
refers to a saturated bicyclic ring system as defined above.
Preferably, 7-, 8- or 9-membered bicyclic heterocycloalkyl is a
monovalent saturated bicyclic ring system containing one or two
ring heteroatoms selected from N, O and S. Thereby, "bicyclic"
describes a system consisting of two saturated rings having two
ring atoms in common, i.e. the bridge separating the two rings is
either a bond or a chain of preferably one or two atoms. Examples
for 7-, 8- or 9-membered bicyclic heterocycloalkyl are
2-oxa-5-aza-hicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,
8-aza-bicyclo[3.2.1]octyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl,
9-aza-bicyclo[3.3.1]nonyl and 3-thia-9-aza-bicyclo[3.3.1]nonyl. 7-,
8- or 9-membered bicyclic heterocycloalkyl is optionally
substituted as described herein.
[0047] The term "10- or 11-membered spirocyclic heterocycloalkyl"
denotes a monovalent bicyclic saturated moiety with the rings
connected through just one atom, containing one, two or three ring
heteroatoms selected from N, O or S. Examples for 10- or
11-membered spirocyclic heterocycloalkyl are
2-oxa-8-aza-spiro[4.5]decanyl and
1,4-dioxa-8-aza-spiro[4.5]decanyl. The 10- or 11-membered
spirocyclic heterocycloalkyl is optionally substituted as described
herein.
[0048] When indicating the number of substituents, the term "one or
more" means from one substituent to the highest possible number of
substitution, i.e. replacement of one hydrogen up to replacement of
all hydrogens by substituents. Thereby, one, two or three
substituents are preferred.
[0049] "Pharmaceutically acceptable," such as pharmaceutically
acceptable carrier, excipient, etc., means pharmacologically
acceptable and substantially non-toxic to the subject to which the
particular compound is administered.
[0050] The term "pharmaceutically acceptable salt" or
"pharmaceutically acceptable acid addition salt" embraces salts
with inorganic and organic acids, such as hydrochloric acid, nitric
acid, sulfuric acid, phosphoric acid, citric acid, formic acid,
fumaric acid, maleic acid, acetic acid, succinic acid, tartaric
acid, methane-sulfonic acid, p-toluenesulfonic acid and the
like.
[0051] "Therapeutically effective amount" means an amount that is
effective to prevent, alleviate or ameliorate symptoms of disease
or prolong the survival of the subject being treated.
[0052] In detail, the present invention relates to compounds of the
general formula (I)
##STR00003##
wherein [0053] A is --CH.sub.2-- or --O--; [0054] R.sup.1 is
hydrogen or alkyl; [0055] R.sup.2 is hydrogen, [0056]
heterocycloalkyl, [0057] --(CH.sub.2).sub.a--R.sup.a, wherein
R.sup.a is hydrogen, alkoxy, hydroxy, cyano, or NR.sup.iR.sup.ii,
wherein R.sup.i and R.sup.ii are each independently hydrogen, alkyl
or C(O)O-alkyl, [0058] allyl, [0059] --C(.dbd.NH)--S--R.sup.b,
wherein R.sup.b is alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,
cyanoalkyl, or alkenyl, [0060] --C(.dbd.NR.sup.c)NR.sup.dR.sup.e,
wherein R.sup.c, R.sup.d, and R.sup.e are each independently
hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or wherein R.sup.d
and R.sup.e together with the nitrogen to which they are bound form
a heterocycloalkyl, [0061] --C(O)R.sup.f, wherein R.sup.f is alkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.b--Oalkyl,
--(CH.sub.2).sub.b-heterocycloalkyl, --O-heterocycloalkyl, or
--(CH.sub.2).sub.b--NR.sup.iiiR.sup.iv, [0062] wherein R.sup.iii
and R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.a--Oalkyl, bicyclic
cycloalkyl, bicyclic cycloalkenyl,
--(CH.sub.2).sub.b-heterocycloalkyl,
--(CH.sub.2).sub.a--O-heterocycloalkyl, or
--(CH.sub.2).sub.a--NR'R'', wherein R' and R'' are each
independently hydrogen, alkyl or cycloalkyl, [0063]
--C(S)NR.sup.vR.sup.vi, wherein R.sup.v and R.sup.vi are each
independently H, alkyl or cycloalkyl, [0064]
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or heterocycloalkyl, [0065]
--S(O).sub.2-heterocycloalkyl, or [0066] R.sup.1 and R.sup.2
together with the N atom to which they are bound form a 5- or
6-membered heterocycloalkyl, [0067] R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are each independently selected from the group consisting
of H, halo, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy,
haloalkoxy, --O-alkylene-O-alkyl, hydroxyl, oxo, cyano, nitro and
NR.sup.ixR.sup.x, wherein R.sup.ix and R.sup.x are each
independently H or alkyl, [0068] a is 1 to 6, [0069] b is 0 to 6,
and [0070] n is 1 or 2, and wherein [0071] heterocycloalkyl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, hydroxy,
hydroxyalkyl, benzyl, oxo, --C(O)Oalkyl, cycloalkyl,
alkylene-O-alkyl, --C(O)haloalkyl, cyanoalkyl,
alkylene-S(O).sub.2-alkyl, -alkylene-C(O)N(alkyl).sub.2, halo,
haloalkyl and alkyoxy; and wherein [0072] cycloalkyl is
unsubstituted or substituted with one or more substituents
independently selected from from the group consisting of alkyl,
hydroxy, hydroxyalkyl, phenyl, oxo, cyanoalkyl,
-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl, halo, and
alkyoxy; [0073] or a pharmaceutically acceptable salt thereof.
[0074] In certain embodiments of formula I, a is 1, 2, 3 or 4,
preferably 2.
[0075] In certain embodiments of formula I, b is 0, 1, 2, 3 or 4;
preferably 0 or 1.
[0076] In certain embodiments of formula I, R.sup.1 is hydrogen or
C.sub.1-4-alkyl, preferably, R.sup.1 is hydrogen.
[0077] In certain embodiments of formula I, R.sup.2 is [0078]
hydrogen, [0079] 5- or 6-membered heterocycloalkyl, [0080]
--(CH.sub.2).sub.a--R.sup.a, wherein R.sup.a is hydrogen, alkoxy,
hydroxy, cyano, or NR.sup.iR.sup.ii, wherein R.sup.i and R.sup.ii
are each independently hydrogen, alkyl or C(O)O-alkyl, [0081]
allyl, [0082] --C(.dbd.NH)--S--R.sup.b, wherein R.sup.b is alkyl,
cycloalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, or alkenyl, [0083]
--C(.dbd.NR.sup.c)NR.sup.dR.sup.e, wherein R.sup.c, R.sup.d, and
R.sup.e are each independently hydrogen, alkyl, cycloalkyl, 5- or
6-membered heterocycloalkyl, or wherein R.sup.d and R.sup.e
together with the nitrogen to which they are bound form a 5- or
6-membered heterocycloalkyl, [0084] --C(O)R.sup.f, wherein R.sup.f
is [0085] alkyl, [0086] --(CH.sub.2).sub.b-cycloalkyl, [0087]
--(CH.sub.2).sub.b--Oalkyl, [0088]
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is a 5- or 6-membered monocycle or a 7-, 8- or 9-membered bicycle,
[0089] --O-heterocycloalkyl, wherein the heterocycloalkyl is a 5-
or 6-membered monocycle, [0090] 10- or 11-membered spirocyclic
heterocycloalkyl, [0091] --(CH.sub.2).sub.b-NR.sup.iiiR.sup.iv,
wherein R.sup.iii and R.sup.iv are each independently [0092]
hydrogen, [0093] alkyl, [0094] --C(O)Oalkyl, [0095]
--(CH.sub.2).sub.b-cycloalkyl, [0096] --(CH.sub.2).sub.a--Oalkyl,
[0097] 7- or 8-membered bicyclic cycloalkyl or cycloalkenyl, [0098]
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is a 5- or 6-membered monocycle or a 7-, 8- or 9-membered bicycle,
[0099] --(CH.sub.2).sub.a--O-heterocycloalkyl, wherein the
heterocycloalkyl is a 5- or 6-membered monocycle, or [0100]
--(CH.sub.2).sub.a--NR'R'', wherein R' and R'' are each
independently hydrogen, alkyl or cycloalkyl, [0101]
--C(S)NR.sup.vR.sup.vi, wherein R.sup.v and R.sup.vi are each
independently H, alkyl or cycloalkyl, [0102]
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or 5- or 6-membered heterocycloalkyl, [0103]
--S(O).sub.2-heterocycloalkyl, wherein the heterocycloalkyl is a 5-
or 6-membered monocycle or a 7-, 8- or 9-membered bicycle, or
[0104] --S(O).sub.2-spirocyclic heteroalkyl, wherein the
spirocyclic heteroalkyl is 10- or 11-membered; [0105] a is 1 to 6,
preferably 1 to 4, [0106] b is 0 to 6, preferably 0 to 4, and
wherein [0107] heterocycloalkyl is unsubstituted or substituted
with one or more substituents independently selected from the group
consisting of alkyl, hydroxy, hydroxyalkyl, benzyl, oxo,
--C(O)Oalkyl, cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl,
cyanoalkyl, alkylene-S(O).sub.2-alkyl,
-alkylene-C(O)N(alkyl).sub.2, halo, haloalkyl and alkyoxy; and
wherein [0108] cycloalkyl is unsubstituted or substituted with one
or more substituents independently selected from the group
consisting of alkyl, hydroxy, hydroxyalkyl, phenyl, oxo,
cyanoalkyl, -alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl,
halo, and alkyoxy.
[0109] In certain embodiments, R.sup.2 is [0110] hydrogen, [0111]
6-membered heterocycloalkyl, [0112]
--(CH.sub.2).sub.a--NR.sup.iR.sup.ii, wherein R.sup.i and R.sup.ii
are each independently hydrogen, alkyl or C(O)O-alkyl, [0113]
allyl, [0114] --C(.dbd.NH)--S-alkyl [0115]
--C(.dbd.NR.sup.c)NR.sup.dR.sup.e, wherein R.sup.c, R.sup.d, and
R.sup.e are each independently hydrogen, alkyl, cycloalkyl,
6-membered heterocycloalkyl, or wherein R.sup.d and R.sup.e
together with the nitrogen to which they are bound form a
6-membered heterocycloalkyl, [0116] --C(O)R.sup.f, wherein R.sup.f
is [0117] alkyl, [0118] --(CH.sub.2).sub.b-cycloalkyl, [0119]
--(CH.sub.2).sub.b--Oalkyl, [0120]
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is a 5- or 6-membered monocycle or a 7-membered bicycle, or [0121]
--O-heterocycloalkyl, wherein the heterocycloalkyl is a 6-membered
monocycle, [0122] 10-membered spirocyclic heterocycloalkyl, [0123]
--(CH.sub.2).sub.b--NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently [0124] hydrogen, [0125] alkyl,
[0126] --C(O)Oalkyl, [0127] --(CH.sub.2).sub.b-cycloalkyl, [0128]
--(CH.sub.2).sub.a--Oalkyl, [0129] 7-membered bicyclic cycloalkyl,
[0130] --(CH.sub.2).sub.b-heterocycloalkyl, wherein the
heterocycloalkyl is a 5- or 6-membered monocycle or a 8- or
9-membered bicycle, [0131] --(CH.sub.2).sub.a--O-heterocycloalkyl,
wherein the heterocycloalkyl is a 6-membered monocycle, or [0132]
--(CH.sub.2).sub.a--NR'R'', wherein R' and R'' are each
independently alkyl or cycloalkyl, [0133] --C(S)NH.sub.2, [0134]
--S(O).sub.2NR.sup.viiR.sup.viii, wherein R.sup.vii and R.sup.viii
are each independently H, alkyl, --C(O)Oalkyl, alkylene-O alkyl,
cycloalkyl, or 6-membered heterocycloalkyl, [0135]
--S(O).sub.2-heterocycloalkyl, wherein the heterocycloalkyl is a 5-
or 6-membered monocycle or a 7-membered bicycle, or [0136]
--S(O)2-spirocyclic heteroalkyl, wherein the spirocyclic
heteroalkyl is 10- or 11-membered, [0137] a is 1 to 6, preferably 1
to 4, [0138] b is 0 to 6, preferably 0 to 4, and wherein [0139]
heterocycloalkyl is unsubstituted or substituted with one or more
substituents independently selected from the group consisting of
alkyl, hydroxy, hydroxyalkyl, benzyl, oxo, --C(O)Oalkyl,
cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl, cyanoalkyl,
alkylene-S(O).sub.2-alkyl, -alkylene-C(O)N(alkyl).sub.2, halo,
haloalkyl and alkyoxy; and wherein [0140] cycloalkyl is
unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, hydroxy,
hydroxyalkyl, phenyl, oxo, cyanoalkyl,
-alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl, haloalkyl, halo, and
alkyoxy,
[0141] In certain embodiments of the compound of formula I, R.sup.2
is [0142] hydrogen, [0143] morpholin-4-yl, 4-methyl-piperazin-1-yl,
or piperazin-1-yl, [0144] --(CH.sub.2).sub.a--NR.sup.iR.sup.ii,
wherein R.sup.i and R.sup.ii are each independently hydrogen, alkyl
or C(O)O-alkyl, allyl, [0145] --C(.dbd.NH)--S-alkyl, [0146]
--C(.dbd.NR.sup.c)NR.sup.dR.sup.e, wherein R.sup.c is H or alkyl,
and R.sup.d and R.sup.e are each independently hydrogen, alkyl,
cycloalkyl, 1-methyl-piperidin-4-yl, piperidin-4-yl, or wherein
R.sup.d and R.sup.e together with the nitrogen to which they are
bound form a morpholine ring, a piperazine ring, or a
4-methyl-piperazine ring, [0147] --C(O)R.sup.f, wherein R.sup.f is
[0148] alkyl, [0149] --(CH.sub.2).sub.b-cycloalkyl, [0150]
--(CH.sub.2).sub.b--Oalkyl, [0151]
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is selected from the group consisting of morpholin-4-yl,
tetrahydropyran-4-yl, 4-methyl-piperazin-1-yl,
4-isopropyl-piperazin-1-yl, piperazin-1-yl, thiomorpholin-4-yl,
4-hydroxy-4-methyl-piperidine-1-yl, (1S
,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl,
(1R,5S)-8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl,
4-hydroxymethyl-piperidine-1-yl, 4-tert-butyl-piperazine-1-yl,
4-methyl-piperidine-1-yl, and piperidine-1-yl, [0152]
--O-heterocycloalkyl, wherein the heterocycloalkyl is
4-methyl-piperidine-1-yl, or piperidine-1-yl, [0153]
2-oxa-8-aza-spiro[4.5]decan-8-yl, [0154]
--(CH.sub.2).sub.b-NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently [0155] hydrogen, [0156] alkyl,
[0157] --C(O)Oalkyl, [0158] --(CH.sub.2).sub.b-cycloalkyl, wherein
cycloalkyl is selected from cyclohexyl, 4-hydroxycyclohexyl,
cyclopropyl, 2-phenyl-cycloprop-1-yl, or cyclopentyl, [0159]
--(CH.sub.2).sub.a--Oalkyl, [0160] --(CH.sub.2).sub.a--NR'R'',
wherein R' and R'' are each independently alkyl or cycloalkyl,
bicyclo[2.2.1]heptanyl, or [0161]
--(CH.sub.2).sub.b-heterocycloalkyl, wherein the heterocycloalkyl
is 4-methyl-piperazin-1-yl, tetrahydro-pyran-4-yl,
1-methyl-piperidin-4-yl, 1-benzyl-pyrrolidin-3-yl,
1,1-dioxo-tetrahydro-thiophen-3-yl, morpholin-4-yl, piperidin-4-yl,
1-tert-butoxycarbonyl-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl,
1-isopropyl-piperidin-4-yl, 1-(2-methoxyethyl)-piperidin-4-yl,
1-(2-fluoroethyl)-piperidin-4-yl,
1-(3,3,3-trifluoropropyl)-piperidin-4-yl,
1-(2-methylsulfanyl-ethyl)-piperidin-4-yl,
3-(endo)-9-methyl-9-aza-bicyclo[3.3.1]non-3-yl,
1-(3,3,3-trifluoro-propionyl)-piperidin-4-yl,
1,1-dioxo-hexahydro-thiopyran-4-yl,
3-endo-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,
1-(2-fluoro-acetyl)-piperidin-4-yl, 1-methyl-pyrrolidin-3-yl,
1-methoxycarbonyl-piperidin-4-yl,
(3-exo)-8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(3-exo)-9-(2,2,2-trifluoro-ethyl)-9-aza-bicyclo[3.3.1]non-3-yl,
(3-exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(7-exo)-9-methyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl,
1-methyl-pyrrolidin-3-yl,
(3-exo)-9-cyclopropyl-9-aza-bicyclo[3.3.1]non-3-yl,
(7-exo)-9-methyl-3-thia-9-aza-bicyclo[3.3.1]non-7-yl,
1-cyanomethyl-piperidin-4-yl,
1-(2-methanesulfonyl-ethyl)-piperidin-4-yl,
(N,N-dimethylamino-carbonylmethylene)-piperidin-4-yl,
1-(2-hydroxy-ethyl)-piperidin-4-yl,
(3-exo)-9-isopropyl-9-aza-bicyclo[3.3.1]non-3-yl,
(3-exo)-8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(3-exo)-8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(1R,5S)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,
(1R,5S)-9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]non-3-yl, or
1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl, [0162]
--C(S)NH.sub.2, [0163] --S(O).sub.2NR.sup.viiR.sup.viii, wherein
R.sup.vii and R.sup.viii are each independently H, alkyl,
--C(O)Oalkyl, alkylene-O alkyl, cycloalkyl, or
tetrahydro-2H-pyran-4-yl, [0164] --S(O).sub.2-heterocycloalkyl,
wherein the heterocycloalkyl is selected from the group consisting
of pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-yl, morpholin-4-yl,
4-methyl-piperazin-1-yl, piperazin-1-yl, thiomorpholin-4-yl,
1,1-dioxo-thiomorpholin-4-yl, 4-methoxymethyl-piperidin-1-yl,
4-methoxy-piperidine-1-yl,
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl,
(1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl, or [0165]
--S(O).sub.2-spirocyclic heteroalkyl, wherein the spirocyclic
heteroalkyl is 2-oxa-8-aza-spiro[4.5]decan-8-yl, or
1,4-dioxa-8-aza-spiro[4.5]decanyl, [0166] a is 1 to 6, preferably 1
to 4, [0167] b is 0 to 6, preferably 0 to 4.
[0168] In certain embodiments of the compound of formula I, [0169]
R.sup.2 is --C(O)R.sup.f, wherein R.sup.f is
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.b-heterocycloalkyl,
or --(CH.sub.2).sub.b-NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.a--Oalkyl, bicyclic
cycloalkyl, bicyclic cycloalkenyl,
--(CH.sub.2).sub.b-heterocycloalkyl, or --(CH.sub.2).sup.a--NR'R'',
wherein R' and R'' are each independently hydrogen, alkyl or
cycloalkyl, [0170] --S(O).sub.2NR.sup.viiR.sup.viii, wherein
R.sup.vii and R.sup.viii are each independently H, alkyl,
--C(O)Oalkyl, alkylene-O alkyl, cycloalkyl, or heterocycloalkyl, or
[0171] --S(O).sub.2-heterocycloalkyl, [0172] a is 1 to 6,
preferably 1 to 4, more preferably 2, [0173] b is 0 to 6,
preferably 0 to 4, more preferably 0 or 1, [0174] heterocycloalkyl
is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of alkyl, hydroxy,
hydroxyalkyl, benzyl, oxo, --C(O)Oalkyl, cycloalkyl,
alkylene-O-alkyl, --C(O)haloalkyl, cyanoalkyl,
alkylene-S(O).sub.2-alkyl, -alkylene-C(O)N(alkyl).sub.2, halo,
haloalkyl and alkyoxy; and [0175] cycloalkyl is unsubstituted or
substituted with one or more substituents independently selected
from the group consisting of alkyl, hydroxy, hydroxyalkyl, phenyl,
oxo, cyanoalkyl, -alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl,
haloalkyl, halo, and alkyoxy.
[0176] In certain embodiments of formula I, R.sup.1 and R.sup.2
together with the nitrogen to which they are bound form a 5- or
6-membered heterocycloalkyl which is unsubstituted or substituted
with one or more substituents independently selected from the group
consisting of alkyl, hydroxy, hydroxyalkyl, benzyl, oxo,
--C(O)Oalkyl, cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl,
cyanoalkyl, alkylene-S(O).sub.2-alkyl,
-alkylene-C(O)N(alkyl).sub.2, halo, haloalkyl and alkyoxy.
[0177] In certain embodiments of formula I, R.sup.1 and R.sup.2
together with the nitrogen to which they are bound form
3-methyl-imidazolidin-2-one or 4-methyl-piperazin-1-yl.
[0178] In certain embodiments of formula I, A is --CH.sub.2-- and n
is 1 or 2, or A is --O-- and n is 1.
[0179] In certain embodiments of formula I, A is --CH.sub.2-- and n
is 1.
[0180] In certain embodiments of formula I, A is --CH.sub.2-- and n
is 2.
[0181] In certain embodiments of formula I, A is --O-- and n is
1.
[0182] In certain embodiments of the compounds of formula I,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above.
[0183] In certain embodiments of the compounds of formula I,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are are independently
selected from the group consisting of H, halo, alkoxy, alkyl,
haloalkoxy, and --O-alkylene-O-alkyl.
[0184] In certain embodiments of the compounds of formula I,
R.sup.3is H, halo or alkyl; preferably H, chloro or methyl.
[0185] In certain embodiments of the compound of formula I,
R.sup.4is H, halo or alkyl; preferably H, fluoro or methyl.
[0186] In certain embodiments of the compound of formula I,
R.sup.5is H or halo; preferably H, fluoro or chloro.
[0187] In certain embodiments of the invention, R.sup.6 is H,
alkoxy, alkyl, halo, or --O-alkylene-O-alkyl; preferably H,
C.sub.1-4-alkoxy, C.sub.1-4-alkyl, fluoro or
--O--CH.sub.2CH.sub.2OMe.
[0188] In certain embodiments, R.sup.3 to R.sup.6 are all H.
[0189] In certain embodiments, R.sup.3 to R.sup.5 are all H and
R.sup.6 is alkoxy, alkyl, halo, or --O-alkylene-O-alkyl.
[0190] In certain embodiments, R.sup.3, R.sup.5 and R.sup.6 are all
H and R.sup.4 is halo, preferably fluoro.
[0191] In certain embodiments, R.sup.3, R.sup.4 and R.sup.6 are all
H and R.sup.5 is halo.
[0192] In certain embodiments I, R.sup.3 and R.sup.5 are chloro,
R.sup.4 is H, and R.sup.6 is methoxy.
[0193] In certain embodiments, R.sup.3is alkyl, R.sup.4 and R.sup.5
are H, and R.sup.6 is alkoxy.
[0194] In certain embodiments, R.sup.3 and R.sup.5is H, R.sup.4is
alkyl and R.sup.6 is alkoxy.
[0195] In certain embodiments, not all R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 are simultaneously H.
[0196] It is to be understood that all combinations of n, A,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 as
disclosed herein are encompassed by present invention.
[0197] Preferred compounds of formula I are those as shown in the
examples below.
[0198] More preferred are the following compounds of formula I:
[0199] 1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea,
[0200] 1-Cyclohexyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea,
[0201] 1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-methyl-urea,
[0202] 1-tert-Butyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea,
[0203] [2-((R)-Indan-1-ylamino)-quinolin-6-yl]-urea, [0204]
rac-1-Isopropyl-3-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-urea,
[0205]
(-)-1-Isopropyl-3-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-ur-
ea, [0206]
rac-1-Isopropyl-3-[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-
-ylamino)-quinolin-6-yl]-urea, [0207]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(2-methoxy-ethyl)-urea,
[0208]
1-(2-Dimethylamino-ethyl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl-
]-urea, [0209]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(tetrahydro-pyran-4-yl)-urea,
[0210]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-piperidin-4--
yl)-urea, [0211]
1-Cyclopropyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea,
[0212]
1-Cyclopropylmethyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea,
[0213]
1-Bicyclo[2.2.1]hept-2-yl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl-
]-urea, [0214]
1-[2-(Cyclopropyl-methyl-amino)-ethyl]-3-[2-((R)-indan-1-ylamino)-quinoli-
n-6-yl]-urea, [0215]
rac-1-[2-(2,3-Dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-(1-methyl-pi-
peridin-4-yl)-urea, [0216]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea,
[0217]
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-piperidin-
-4-yl)-urea, [0218]
1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl-
]-urea, [0219]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperidin-4-yl)--
urea, [0220]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methoxy-ethyl)-piperidi-
n-4-yl]-urea, [0221]
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-quino-
lin-6-yl]-urea, [0222]
rac-1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamin-
o)-quinolin-6-yl]-urea, [0223]
rac-1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamino-
)-quinolin-6-yl]-urea, [0224]
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-
-propyl)-piperidin-4-yl]-urea, [0225]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methylsulfanyl-ethyl)-p-
iperidin-4-yl]-urea, [0226]
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-(9-methyl-9-aza-bic-
yclo[3.3.1]non-3-yl)-urea, [0227]
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methylsulfany-
l-ethyl)-piperidin-4-yl]-urea, [0228]
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-
-propionyl)-piperidin-4-yl]-urea, [0229]
rac-1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-qui-
nolin-6-yl]-urea, [0230]
rac-1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-(8-methoxy-1,2,3,4-tetrahydro-n-
aphthalen-1-ylamino)-quinolin-6-yl]-urea, [0231]
rac-1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-y-
l]-3-(1-methyl-piperidin-4-yl)-urea, [0232]
rac-1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-3-[2-(8-methoxy-1,2,3,4-tetrah-
ydro-naphthalen-1-ylamino)-quinolin-6-yl]-urea, [0233]
rac-1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-(8-methoxy-1,2,3,4-tetrahy-
dro-naphthalen-1-ylamino)-quinolin-6-yl]-urea, [0234]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-propyl)-p-
iperidin-4-yl]-urea, [0235]
N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N,N-dimethylsul-
famide, [0236]
rac-N'-{2-[(7-methoxy-2,3-dihydro-1H-inden-1-yl)amino]quinolin-6-yl}-N,N--
dimethylsulfamide, [0237]
N-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}sulfamide
hydrochloride, [0238] Pyrrolidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide, [0239]
3,3-Difluoro-pyrrolidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide, [0240]
(2-Methoxy-ethyl)-methyl-sulfonic acid
[2-((R)-indan-1-ylamino)quinolin-6-yl]-amide, [0241]
Morpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide, [0242]
Thiomorpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide, [0243]
1,4-Dioxa-8-aza-spiro[4.5]decane-8-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide, [0244]
N-cyclopropyl-N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N-
-methylsulfamide, [0245]
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide, [0246]
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-ami-
de, [0247]
rac-1-Isopropyl-3-[2-(7-methoxy-4-methyl-indan-1-ylamino)-quino-
lin-6-yl]-urea, [0248]
1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinolin-
-6-yl]-urea, [0249]
1-((3-exo)-8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-((R)-indan-1--
ylamino)-quinolin-6-yl]-urea, [0250]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-8-methyl-8-aza-bicyc-
lo[3.2.1]oct-3-yl)-urea, [0251]
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea,
[0252] 1-((3-exo)-9-Cyclopropyl-9-aza-bicyclo[3.3.1
]non-3-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea, [0253]
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperid-
in-4-yl)-urea, [0254]
rac-1-Isopropyl-3-[2-(7-methoxy-5-methyl-indan-1-ylamino)-quinolin-6-yl]--
urea, [0255]
rac-1-[2-(7-Methoxy-5-methyl-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl--
piperidin-4-yl)-urea, [0256]
1-(1-Cyanomethyl-piperidin-4-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl-
]-urea, [0257]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methanesulfonyl-ethyl)--
piperidin-4-yl]-urea, [0258]
2-(4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidin-1-yl)-N-
,N-dimethyl-acetamide, [0259]
1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinoli-
n-6-yl]-urea, [0260]
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-carbamic acid isopropyl
ester, [0261]
rac-N-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-
-1-yl)-acetamide, [0262] rac-Cyclopropanecarboxylic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide, [0263]
rac-Cyclopropanecarboxylic acid
[2-(5-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide, [0264]
rac-1-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea,
[0265] (1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide, [0266]
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-thiourea, [0267]
rac-1-[2-(6-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperid-
in-4-yl)-urea, [0268]
rac-1-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperid-
in-4-yl)-urea, [0269] rac-Cyclopropanecarboxylic acid
[2-(7-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide, [0270]
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-N',N''-diisopropyl-guanidine,
[0271]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-9-isopropyl-9-
-aza-bicyclo[3.3.1]non-3-yl)-urea, [0272]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-8-isopropyl-8-aza-bi-
cyclo[3.2.1]oct-3-yl)-urea, [0273]
rac-N.sup.2-(7-Methoxy-indan-1-yl)-quinoline-2,6-diamine, [0274]
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-quino-
lin-6-yl]-1-methyl-urea, [0275]
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benzofuran-
-3-ylamino)-quinolin-6-yl]-urea, [0276]
rac-1-[2-(4-Ethoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-(1--
isopropyl-piperidin-4-yl)-urea, [0277]
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(7-methoxy--
indan-1-ylamino)-quinolin-6-yl]-urea, [0278]
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(7-methoxy--
indan-1-ylamino)-quinolin-6-yl]-1-methyl-urea, [0279]
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamin-
o)-quinolin-6-yl]-urea, [0280]
rac-1-[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-3-[2-(7-methoxy-inda-
n-1-ylamino)-quinolin-6-yl]-1-methyl-urea, [0281]
rac-Cyclopropanecarboxylic acid
[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-amide,
[0282]
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-hydroxy-
-ethyl)-piperidin-4-yl]-urea, [0283]
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamin-
o)-quinolin-6-yl]-1-methyl-urea, and [0284]
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-1-yl)-ace-
tamide.
[0285] The present compounds of formula I, their starting
materials, their pharmaceutically acceptable salts, and their
optical isomers can be prepared by methods known in the art. For
example, a process to synthesize representative compounds of
formula I can be used which comprises one of the following steps:
2,6-Dichloroquinoline (a) is reacted with a compound of formula (b)
to give an intermediate of formula (c), which is subsequently
reacted with amine H.sub.2N(CH.sub.2).sub.a--R.sup.a to give
product compound (Ia), shown in subsequent scheme 1:
##STR00004##
R.sup.a, a, n, A and R.sup.3 to R.sup.6 are as described above.
[0286] Moreover, and as may be seen from Scheme 2, compounds of
present invention can be synthesized by reacting
2-chloro-6-nitro-quinoline (d) with a compound of formula (b) to
give intermediate (e), which is subsequently reduced with hydrogen
and palladium on carbon under normal pressure to yield an amine of
formula (f). The compound of formula (f) is then either reacted
with a compound R.sup.2-LG wherein LG denotes a leaving group such
as halo or imidazolyl, to give the product of formula Ib.
Alternatively, compound (f) is reacted with R.sup.2--OH in the
presence of a peptide coupling reagent such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
dicyclohexylcarbodiimide, or a carbodiimide in combination with
1-hydroxybenzotriazole.
##STR00005##
A, n, and R.sup.3 to R.sup.6 are as described above and R.sup.2 is
preferably [0287] --C(O)R.sup.f, wherein R.sup.f is [0288]
--(CH.sub.2).sub.b-cycloalkyl, [0289]
--(CH.sub.2).sub.b-heterocycloalkyl, or [0290]
--(CH.sub.2).sub.b-NR.sup.iiiR.sup.iv, wherein R.sup.iii and
R.sup.iv are each independently hydrogen, alkyl, --C(O)Oalkyl,
--(CH.sub.2).sub.b-cycloalkyl, --(CH.sub.2).sub.a--Oalkyl, bicyclic
cycloalkyl, bicyclic cycloalkenyl,
--(CH.sub.2).sub.b-heterocycloalkyl, or --(CH.sub.2).sub.a--NR'R'',
wherein R' and R'' are each independently hydrogen, alkyl or
cycloalkyl, [0291] --S(O).sub.2NR.sup.viiR.sup.viii, wherein
R.sup.vii and R.sup.viii are each independently H, alkyl,
--C(O)Oalkyl, alkylene-O alkyl, cycloalkyl, or heterocycloalkyl, or
[0292] --S(O).sub.2-heterocycloalkyl, [0293] a is 1 to 6,
preferably 1 to 4, more preferably 2, [0294] b is 0 to 6,
preferably 0 to 4, more preferably 0 or 1, [0295] n is 1 or 2, and
[0296] heterocycloalkyl is unsubstituted or substituted with one or
more substituents independently selected from the group consisting
of alkyl, hydroxy, hydroxyalkyl, benzyl, oxo, --C(O)Oalkyl,
cycloalkyl, alkylene-O-alkyl, --C(O)haloalkyl, cyanoalkyl,
alkylene-S(O).sub.2-alkyl, -alkylene-C(O)N(alkyl).sub.2, halo,
haloalkyl and alkyoxy; and [0297] cycloalkyl is unsubstituted or
substituted with one or more substituents independently selected
from the group consisting of alkyl, hydroxy, hydroxyalkyl, phenyl,
oxo, cyanoalkyl, -alkylene-C(O)N(alkyl).sub.2, hydroxyalkyl,
haloalkyl, halo, and alkyoxy.
[0298] As mentioned earlier, the compounds of formula I and their
pharmaceutically acceptable addition salts possess valuable
pharmaceutical properties. Compounds of the present invention are
active on the 5-HT.sub.5A receptor and therefore suitable for the
treatment of depression, anxiety disorders, schizophrenia, panic
disorders, agoraphobia, social phobia, obsessive compulsive
disorders, post-traumatic stress disorders, pain, memory disorders,
dementia, disorders of eating behaviors, sexual dysfunction, sleep
disorders, withdrawal from abuse of drugs, motor disorders such as
Parkinson's disease, psychiatric disorders or gastrointestinal
disorders.
Test Description
[0299] A [.sup.3H]LSD radioligand binding assay was used to
determine the affinity of the compounds for the recombinant human
5-HT.sub.5A receptor, in membranes from transiently (cDNA)
expressed 5-HT.sub.5A receptors in Human Embryonic Kidney-EBNA
(HEK-EBNA) cells. Assay buffer consisted of Tris (50 mM) buffer
containing 1 mM EGTA, 10 mM MgCl.sub.2 (pH 7.4) and 10 .mu.M
pargyline. The binding assay was carried out in 96-well-plates in
the presence of [.sup.3H]LSD (approximately 1 nM), approximately 2
.mu.g/well of membrane protein, and 0.5 mg of Ysi-poly-1-lysine SPA
beads in a final volume of 200 .mu.l of buffer. Non-specific
binding was defined using methiothepin 2 .mu.M. Compounds were
tested at 10 concentrations. All assays were conducted in duplicate
and repeated at least two times. Assay plates were incubated for
120 min at room temperature before centrifugation. Bound ligand was
determined using a Packard Topcount scintillation counter.
IC.sub.50 values were calculated using a non-linear curve fitting
program and Ki values calculated using the Cheng-Prussoff
equation.
[0300] The activity of the compounds according to the invention is
exemplified in the table 1 below:
TABLE-US-00001 Ki/nM Example 5-HT.sub.5A 3 2.5 5 2.9 7 3.4 8 10.9 9
2.9 12 1.5 13 0.9 15 7.7 17 7.0 18 7.3 19 4.0 20 1.8 21 3.9 23 4.7
26 4.8 32 8.2 35 9.6 39 3.9 40 2.2 41 4.1 42 2.4 43 2.5 44 3.0 45
3.0 46 2.7 47 3.0 48 7.7 50 5.2 51 3.9 52 7.5 53 3.1 55 9.7 57 5.8
58 5.3 59 5.9 63 10.4 66 5.6 68 2.5 72 8.4 73 3.2 74 8.9 75 8.3 76
9.9 78 7.0 82 22.2 85 9.3 88 2.5 91 6.8 93 8.7 97 2.9 99 3.9 101
3.7 107 4.4 110 7.2 115 4.0 130 3.4 131 2.9 133 4.2 135 5.7 136 6.5
137 1.7 138 8.0 139 4.4 140 2.2 141 8.6 146 6.1 148 2.1 149 14.8
155 6.3 156 3.8 162 8.3 166 33.7 168 7.8 170 7.1 172 3.3 179 7.1
180 2.8 181 4.1 186 5.7 188 8.5 189 1.8 191 6.9 195 7.3 197 3.5 206
6.7 210 6.7
[0301] The present invention also provides pharmaceutical
compositions containing compounds of the invention, for example,
compounds of formula I or pharmaceutically acceptable salts thereof
and a pharmaceutically acceptable carrier. Such pharmaceutical
compositions can be in the form of tablets, coated tablets,
dragees, hard and soft gelatin capsules, solutions, emulsions or
suspensions. The pharmaceutical compositions also can be in the
form of suppositories or injectable solutions.
[0302] The pharmaceutical compositions of the invention, in
addition to one or more compounds of the invention, contain a
pharmaceutically acceptable carrier. Suitable pharmaceutically
acceptable carriers include pharmaceutically inert, inorganic or
organic carriers. Lactose, corn starch or derivatives thereof,
talc, stearic acids or its salts and the like can be used, for
example, as such carriers for tablets, coated tablets, dragees and
hard gelatine capsules. Suitable carriers for soft gelatine
capsules are, for example, vegetable oils, waxes, fats, semi-solid
and liquid polyols and the like. Depending on the nature of the
active substance no carriers are however usually required in the
case of soft gelatine capsules. Suitable carriers for the
production of solutions and syrups are, for example, water,
polyols, glycerol, vegetable oil and the like. Suitable carriers
for suppositories are, for example, natural or hardened oils,
waxes, fats, semi-liquid or liquid polyols and the like.
[0303] The pharmaceutical compositions can, moreover, contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0304] The present invention also provides a method for the
manufacture of pharmaceutical compositions. Such process comprises
bringing one or more compounds of formula I and/or pharmaceutically
acceptable acid addition salts thereof and, if desired, one or more
other therapeutically valuable substances into a galenical
administration form together with one or more therapeutically inert
carriers.
[0305] The most preferred indications in accordance with the
present invention are those, which include disorders of the central
nervous system, for example the treatment of anxiety, depression,
sleep disorders and schizophrenia.
[0306] The dosage at which compounds of the invention can be
administered can vary within wide limits and will, of course, have
to be adjusted to the individual requirements in each particular
case. In the case of oral administration the dosage for adults can
vary from about 0.01 mg to about 1000 mg per day of a compound of
general formula I or of the corresponding amount of a
pharmaceutically acceptable salt thereof. The daily dosage can be
administered as single dose or in divided doses and, in addition,
the upper limit can also be exceeded when this is found to be
indicated.
Tablet Formulation (Wet Granulation)
TABLE-US-00002 [0307] mg/tablet Item Ingredients 5 mg 25 mg 100 mg
500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous
DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline
Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167
167 831 Manufacturing Procedure 1. Mix items 1, 2, 3 and 4 and
granulate with purified water. 2. Dry the granules at 50.degree. C.
3. Pass the granules through suitable milling equipment. 4. Add
item 5 and mix for three minutes; compress on a suitable press.
Capsule Formulation
TABLE-US-00003 [0308] mg/capsule Item Ingredients 5 mg 25 mg 100 mg
500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159
123 148 -- 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5.
Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing
Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30
minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a
suitable capsule.
[0309] Preparation of the compounds of present invention: Compounds
of formula I may be prepared as shown in the following
description:
Route 1 Described in Example 1
##STR00006##
[0311] 2,6-Dichloro-quinoline (CAS no.: 1810-72-6) is heated with
R-(-)-1-aminoindane to yield intermediate 2 which is subsequently
cross-coupled with N,N-dimethyl-1.3-propanediamine under
palladium-catalyzed conditions to the final product 3.
Route 2 Described in Example 2
##STR00007##
[0313] 2-Chloro-6-nitro-quinoline (CAS no.: 29969-57-1) is treated
with R-(-)-1-aminoindane to yield compound 5 which is then reduced
with hydrogen and palladium on carbon under normal pressure to
yield 6-amino-quinoline derivative 6.
Route 3 Described in Example 3
##STR00008##
[0315] 6-Amino-2-indanoyl-quinoline 6 is treated with isopropyl
isocyanate in toluene to yield urea derivative 7.
Route 4 Described in Example 16 (Alternative Procedure in Example
170)
##STR00009##
[0317] 6-Amino-2-indanoyl-quinoline 6 is treated with
N-methyl-piperazine, triphosgene and triethylamine in
tetrahydrofuran to yield urea derivative 8. Alternatively
6-amino-2-indanoyl-quinoline 6 is treated with N-methyl-piperazine,
4-nitrophenylchloroformate and diisopropyethylamine in
dichloromethane to yield urea derivative 8.
Route 5 Described in Example 66
##STR00010##
[0319] 6-Amino-2-indanoyl-quinoline 6 is treated with dimethyl
sulfamoyl chloride in pyridine to yield sulfamide derivative 9.
Route 6 Described in Example 71 and 72
##STR00011##
[0321] Amino-2-indanoyl-quinoline 6 is treated with dimethylamino
pyridinium N-tert butoxycarbonyl sulfamide and subsequently
deprotected with HCl/Methanol to yield quinoline sulfamide 11.
Route 7 Described in Example 76
##STR00012##
[0323] 1H-Imidazolium, 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-,
trifluoromethanesulfonate (1:1) is treated with morpholine, then
with methyl triflate and subsequently with
amino-2-indanoyl-quinoline 6 to yield morpholino sulfamide 12.
Route 8 Described in Example 9
##STR00013##
[0325] 6-Amino-2-indanoyl-quinoline 6 is treated with potassium
isocyanate in a mixture of acetic acid and water to yield urea
derivative 13.
Route 9 Described in Example 116
##STR00014##
[0327] 6-Amino-2-indanoyl-quinoline 6 is treated with isobutyryl
chloride in triethyl amine and toluene to yield carboxamide
derivative 14.
Route 10 Described in Examples 122 and 123
##STR00015##
[0329] 6-Amino-2-indanoyl-quinoline 6 is treated with N-Boc-glycine
and
1-hydroxybenzotriazole/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride in tetrahydrofuran and subsequently intermediate 15
deprotected with trifluoroacetic acid in dichloromethane to yield
carboxamide 16.
Route 11 Described in Example 138
##STR00016##
[0331] 6-Amino-2-indanoyl-quinoline 6 is treated with isopropyl
chloroformate in toluene and triethyl amine to yield carbamate
derivative 17.
Route 12 Described in Example 166
##STR00017##
[0333] 6-Amino-2-indanoyl-quinoline 6 is treated with N,N
diisopropyl carbodiimide in toluene to yield guanidine derivative
18.
Route 13 Described in Example 149
##STR00018##
[0335] 6-Amino-2-indanoyl-quinoline 6 is treated with
benzoyl-isothiocyanate to yield the intermediate 19 which is
hydrolyzed with sodium hydroxide to the thiourea 20.
Route 14 Described in Example 119
##STR00019##
[0337]
rac-N.sup.2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinolin-
e-2,6-diamine 21 is treated with N,N-dimethylglycine,
N,N-diisopropyl ethyl amine and
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate to yield carboxamide derivative 22.
Route 15 Described in Example 150
##STR00020##
[0339] Thiourea 20 is treated with methyl iodide to yield
1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea
hydroiodide 23.
Route 16 Described in Example 151
##STR00021##
[0341] Thiourea 23 is treated with morpholine to yield the
guanidine 24.
Route 17 Described in Example 163
##STR00022##
[0343] Commercially available 6-bromo-2-chloro-quinoline (25) is
heated with commercially available (R)-1-aminoindane to yield
intermediate 26 which is subsequently cross-coupled with amines
under palladium-catalyzed conditions to the final products 27.
Route 18 Described in Examples 108, 109 and 114
##STR00023##
[0345] 6-Amino-2-indanoyl-quinoline 6 is reductively aminated with
methyl-(2-oxo-ethyl)carbamic acid tert-butyl ester by treatment
with sodium cyanoborohydride, subsequently intermediate 28 is
deprotected with trifluoroacetic acid in dichloromethane to yield
amine 29, which is cyclized to the urea 30.
Route 19 Described in Examples 213
##STR00024##
[0347] N-2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine 31 is
reacted with chloroacetyl chloride to the chloride 32. Treatment
with an amine HNR.sub.2 leads to compound 33.
EXAMPLES
Example 1
N.sup.6-(3-Dimethylamino-propyl)-N.sup.2--(R)-indan-1-yl-quinoline-2,6-dia-
mine
[0348] Step A: 2,6-Dichloroquinoline (5.0 g, 25 mmol) and
R-(-)-1-aminoindane (6.725 g, 50 mmol) were heated at 125.degree.
C. for 20 h. The reaction mixture was purified by flash
chromatography on silica gel (heptane/ethyl acetate
100:0.fwdarw.70:30 gradient).
(6-Chloro-quinolin-2-yl)-(R)-indan-1-yl-amine was obtained as a
light red solid (2.25 g, 30%), MS: m/e=296.8 (M+H.sup.+).
[0349] Step B: (6-Chloro-quinolin-2-yl)-(R)-indan-1-yl-amine (200
mg, 0.75 mmol) was dissolved in 2.5 mL toluene. Argon was bubbled
through the solution for 2 minutes to remove oxygen.
N,N-dimethyl-1,3-propanediamine (0.26 mL, 1.53 mmol), sodium
tert.-butylate (157 mg, 2.4 mmol), palladium acetate (15 mg) and
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS) (49
mg, 0.05 mmol) were added. The reaction mixture was stirred in a
sealed tube at 125.degree. C. for 20 h. The solvent was evaporated
and the residue purified by flash chromatography on silica gel
(ethyl acetate/heptane 50:50.fwdarw.100:0 gradient). The title
compound was obtained as a yellow solid (15 mg, 6%), MS: m/e=361.1
(M+H.sup.+).
Example 2
(R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine
[0350] Step A: 2-Chloro-6-nitro-quinoline (2.0 g, 10 mmol) and
R-(-)-1-aminoindane (3.19 g, 24 mmol) were heated at 130.degree. C.
for 24 h. The reaction mixture was purified by flash chromatography
on silica gel (dichloromethane).
(R)-Indan-1-yl-(6-nitro-quinolin-2-yl)-amine was obtained as a
yellow solid (2.0 g, 68%), MS: m/e=306.8 (M+H.sup.+).
[0351] Step B: (R)-Indan-1-yl-(6-nitro-quinolin-2-yl)-amine (1.5 g,
5.0 mmol) were dissolved in ethyl acetate (60 mL). Upon addition of
palladium on carbon (10%) the reaction mixture was stirred for 2 h
at ambient temperature under an atmosphere of hydrogen. Then the
catalyst was filtered off, the filter washed with ethyl acetate and
the filtrate evaporated.
(R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine was obtained as a
yellow foam (1.3 g, 96%); MS: m/e=276.4 (M+H.sup.+).
Example 3
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea
[0352] (R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine (0.30 g, 1.09
mmol) was dissolved in toluene (5 mL). Isopropyl isocyanate (0.93
g, 1.09 mmol) was added and the reaction mixture was stirred at
60.degree. C. for 2 h. Upon cooling to room temperature a
precipitation formed which was filtered off and washed twice with
dichloromethane. After drying the title compound was obtained as a
white solid (330 mg, 85%); MS: m/e=276.4 (M+H.sup.+).
Example 4
N.sup.6-Allyl-N.sup.2--(R)-indan-1-yl-quinoline-2,6-diamine
[0353] Step A: (R)-Indan-1-yl-(6-iodo-quinolin-2-yl)-amine, MS:
m/e=387.0 (M+H.sup.+), was prepared in accordance with the general
method step A of example 1 from 2-chloro-6-iodoquinoline and
R-(-)-1-aminoindane.
[0354] Step B: The title compound, MS:m/e=316.3 (M+H.sup.+), was
prepared according to step B of the general method of example 1
from (R)-indan-1-yl-(6-iodo-quinolin-2-yl)-amine.
Example 5
1-Cyclohexyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea
[0355] Cyclohexyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea,
MS: m/e=401.5 (M+H.sup.+), was prepared in accordance with the
general method of example 3 from cyclohexyl isocyanate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine.
Example 6
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((1S,2R)-2-phenyl-cyclopropyl)-
-urea
[0356]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((1S,2R)-2-phenyl-cyclo-
propyl)-urea, MS: m/e=435.5 (M+H.sup.+), was prepared in accordance
with the general method of example 3 from trans-2-phenylcyclopropyl
isocyanate and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine.
Example 7
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-methyl-urea
[0357] 1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-methyl-urea, MS:
m/e=332.4 (M+H.sup.+), was prepared in accordance with the general
method of example 3 from methyl isocyanate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine.
Example 8
1-tert-Butyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea
[0358] tert-Butyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea,
MS: m/e=375.4 (M+H.sup.+), was prepared in accordance with the
general method of example 3 from tert. butyl isocyanate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine.
Example 9
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-urea
[0359] (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.36
mmol) and potassium isocyanate (32 mg, 0.40 mmol) were stirred in a
1:1 mixture of water and acetic acid (3 mL) at ambient temperature
for 2 h. Then a satured solution of sodium bicarbonate was added,
the aqueous phase was extracted with ethyl acetate, the organic
phase washed with brine and dried over sodium sulfate. Over night
the desired product precipitated and subsequently the crystals were
collected and dried under vacuum.
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-urea was obtained as a
white solid (44 mg; 38%); MS: m/e=319.3 (M+H.sup.+).
Example 10
rac-1-[2-(2,3-Dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-isopropyl-ure-
a
[0360] Step A:
(2,3-Dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine was
prepared according to step A in general example 2 from
2-chloro-6-nitro-quinoline and 2,3-dihydro-benzofuran-3-ylamine
(CAS no.: 109926-23-4); MS: m/e=308.3 (M+H.sup.+).
[0361] Step B:
N.sup.2-(2,3-Dihydro-benzofuran-3-yl)-quinoline-2,6-diamine was
prepared according to step B in general example 2 from
(2,3-Dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine; MS:
m/e=277.3 (M+H.sup.+).
[0362] Step C: The title compound was prepared in accordance with
the general method described in example 3 from isopropyl isocyanate
and N.sup.2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine;
MS: m/e=363.3 (M+H.sup.+).
Example 11
(+)-1-{2-[-(2,3-Dihydro-benzofuran-3-yl)amino]-quinolin-6-yl}-3-isopropyl--
urea
[0363]
rac-1-[2-(2,3-Dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-isopro-
pyl-urea was separated on chiral preparative HPLC using 15% ethanol
in heptane.
Example 12
rac-1-Isopropyl-3-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-urea
[0364] The title compound was prepared in accordance with the
general method described in example 3 from isopropyl isocyanate and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=391.5 (M+H.sup.+).
Example 13
(-)-1-Isopropyl-3-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-urea
[0365]
rac-1-Isopropyl-3-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-ure-
a was separated on chiral preparative HPLC using 20% ethanol in
heptane.
Example 14
rac-N.sup.2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-d-
iamine
[0366] The title compound was prepared in accordance with the
general method described in example 2 from
2-chloro-6-nitro-quinoline and
rac-8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine (CAS no.
535935-61-6); MS: m/e=320.3 (M+H.sup.+).
Example 15
rac-1-Isopropyl-3-[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-q-
uinolin-6-yl]-urea
[0367] The title compound was prepared in accordance with the
general method described in example 3 from
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine and isopropyl isocyanate; MS: m/e=405.5 (M+H.sup.+).
Example 16
4-Methyl-piperazine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0368] (R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine (0.25 g, 0.9
mmol) was dissolved in tetrahydrofuran (10 mL) and triethylamine
(0.138 mL, 1.0 mmol) was added. At 0.degree. C. triphosgene (121
mg, 0.4 mmol) was added and the reaction mixture subsequently
heated to 80.degree. C. for 3 h. Upon cooling to ambient
temperature triethylamine (0.138 mL, 1.0 mmol) and
1-methyl-piperazine (0.1 mL, 0.9 mmol) were added and the whole
reaction mixture was stirred over night at 50.degree. C. After
evaporation of the solvent, the residue was taken up in water and
extracted with ethyl acetate. The combined organic phases were
dried on sodium sulfate, filtered and the filtrate was evaporated.
The residue was taken up in a small amount of ethyl acetate,
sonicated and kept over night in a refrigerator whereby a
crystalline precipitate formed. The precipitate was isolated and
dried on vacuum to yield the title compound (190 mg; 52%) as an
off-white solid; MS: m/e=402.6 (M+H.sup.+).
Example 17
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(2-methoxy-ethyl)-urea
[0369] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 2-methoxyethylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=377.5
(M+H.sup.+).
Example 18
1-(2-Dimethylamino-ethyl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea
[0370] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 2-dimethylamino-ethylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=390.5
(M+H.sup.+).
Example 19
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(tetrahydro-pyran-4-yl)-urea
[0371] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 4-aminotetrahydropyran and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=403.5
(M+H.sup.+).
Example 20
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-piperidin-4-yl)-urea
[0372] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-methyl-piperidin-4-ylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=415.5
(M+H.sup.+).
Example 21
1-Cyclopropyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea
[0373] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, cyclopropylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=359.5
(M+H.sup.+).
Example 22
Morpholine-4-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0374] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, morpholine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=389.5
(M+H.sup.+).
Example 23
1-Cyclopropylmethyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea
[0375] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, aminomethyl cyclopropane and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=373.5
(M+H.sup.+).
Example 24
Thiomorpholine-4-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0376] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, thiomorpholine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=405.5
(M+H.sup.+).
Example 25
1-(1-Benzyl-pyrrolidin-3-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-ure-
a
[0377] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, rac-1-benzyl-3-aminopyrrolidine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=478.6
(M+H.sup.+).
Example 26
1-Bicyclo[2.2.1]hept-2-yl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-urea
[0378] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, rac-exo-2-aminonorbornane and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=413.6
(M+H.sup.+).
Example 27
1-(1,1-Dioxo-tetrahydro-thiophen-3-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-
-6-yl]-urea
[0379] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, rac-1,1-dioxo-tetrahydro-1-6-thiophen-3-ylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=437.6
(M+H.sup.+).
Example 28
1-Ethyl-1-(4-hydroxy-cyclohexyl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-
-urea
[0380] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 4-ethylamino-cyclohexanol and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=445.7
(M+H.sup.+).
Example 29
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(2-morpholin-4-yl-ethyl)-urea
[0381] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 2-morpholin-4-yl-ethylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=432.6
(M+H.sup.+).
Example 30
4-Hydroxy-4-methyl-piperidine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0382] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 4-methyl-piperidin-4-ol and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=417.6
(M+H.sup.+).
Example 31
2-Oxa-8-aza-spiro[4.5]decane-8-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0383] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 2-(3-ethyl-tetrahydro-furan-3-yl)-ethylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=443.7
(M+H.sup.+).
Example 32
1-[2-(Cyclopropyl-methyl-amino)-ethyl]-3-[2-((R)-indan-1-ylamino)-quinolin-
-6-yl]-urea
[0384] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, N(1)-cyclopropyl-N(1)-methyl-ethane-1,2-diamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=416.6
(M+H.sup.+).
Example 33
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0385] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=401.6
(M+H.sup.+).
Example 34
(1R,5S)-8-Oxa-3-aza-bicyclo[3.2.1]octane-3-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0386] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 8-oxa-3-aza-bicyclo[3.2.1]octane and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=415.6
(M+H.sup.+).
Example 35
rac-1-[2-(2,3-Dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-(1-methyl-pip-
eridin-4-yl)-urea
[0387] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-methyl-piperidin-4-ylamine and
rac-N.sup.2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine;
MS: m/e=418.6 (M+H.sup.+).
Example 36
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[2-(tetrahydro-pyran-2-yloxy)--
ethyl]-urea
[0388] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 2-(tetrahydro-pyran-2-yloxy)-ethylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=446.6
(M+H.sup.+).
Example 37
4-Hydroxymethyl-piperidine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0389] Step A:
4-(Tetrahydro-pyran-2-yloxymethyl)-piperidine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide, MS: m/e=501.7
(M+H.sup.+), was prepared according to general method 4 described
in example 16 from bis(trichloromethyl) carbonate,
4-(tetrahydro-pyran-2-ylmethoxy)-piperidine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine.
[0390] Step B:
4-(Tetrahydro-pyran-2-yloxymethyl)-piperidine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide (0.070 g) was
dissolved in methanol (1 mL). Pyridinium toluene-4-sulfonate (11.0
mg) was added and the reaction mixture stirred at 55.degree. C. for
1 h. The reaction mixtures was diluted with water and extracted
with ethyl acetate. The combined organic phases were dried on
sodium sulfate, evaporated and the residue was subjected to column
chromatography (silica gel, dichloro methane:methanol
gradient=100:0.fwdarw.90:10) to yield the title compound (35 mg;
60%) as an off-white solid; MS: m/e=416.7 (M+H.sup.+).
Example 38
4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidine-1-carboxyl-
ic acid tert-butyl ester
[0391] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 4-amino-1-tert-butyloxycarbonyl-piperidine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=502.6
(M+H.sup.+).
Example 39
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea
[0392]
4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidine-1-c-
arboxylic acid tert-butyl ester (20 mg, 0.040 mmol) was dissolved
in methylene chloride (1.0 mL). At 0.degree. C. trifluoroacetic
acid (0.030 mL, 0.40 mmol) was added and the reaction mixture was
stirred at ambient temperature over night. 20% sodium carbonate
solution in water was added and the mixture was extracted with
ethyl acetate (3.times.10 mL). The combined organic phases were
dried on magnesium sulfate, filtered and evaporated. The residue
was subjected to column chromatography (silica gel, methylene
chloride:methanol gradient=95:5.fwdarw.2:1) to yield the title
compound (5.0 mg; 31%) as an off-white solid; MS: m/e=402.5
(M+H.sup.+).
Example 40
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-piperidin--
4-yl)-urea
[0393] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-methyl-piperidin-4-ylamine and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=446.7 (M+H.sup.+).
Example 41
1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-
-urea
[0394] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-cyclopropyl-piperidin-4-ylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=442.7
(M+H.sup.+).
Example 42
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperidin-4-yl)-u-
rea
[0395] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no. 127285-08-9)
and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=444.7
(M+H.sup.+).
Example 43
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methoxy-ethyl)-piperidin-
-4-yl]-urea
[0396] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2-methoxy-ethyl)-piperidin-4-ylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=460.7
(M+H.sup.+).
Example 44
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-quinol-
in-6-yl]-urea
[0397] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no. 127285-08-9)
and rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine
(Example 172); MS: m/e=474.7 (M+H.sup.+).
Example 45
rac-1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamino-
)-quinolin-6-yl]-urea
[0398] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2-methoxy-ethyl)-piperidin-4-ylamine and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=490.7 (M+H.sup.+).
Example 46
rac-1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamino)-
-quinolin-6-yl]-urea
[0399] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2-fluoroethyl)-piperidin-4-ylamine and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=478.7 (M+H.sup.+).
Example 47
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro--
propyl)-piperidin-4-yl]-urea
[0400] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(3,3,3-trifluoro-propyl)-piperidin-4-ylamine and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=528.8 (M+H.sup.+).
Example 48
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methylsulfanyl-ethyl)-pi-
peridin-4-yl]-urea
[0401] Step A: Piperidin-4-yl-carbamic acid tert-butyl ester (0.70
g, 3.0 mmol), triethylamine (1.46 mL, 10 mmol) and
2-chlorethyl-methylsulfide (0.39 g, 3.0 mmol) were dissolved in
methanol (10 mL) and stirred for 16 h at 50.degree. C. Then the
solvent was removed and the residue subjected to column
chromatography (silica gel, heptane:ethyl acetate
gradient=1:1.fwdarw.0:1).
[1-(2-Methylsulfanyl-ethyl)-piperidin-4-yl]-carbamic acid
tert-butyl ester was obtained as a light yellow solid (0.46 g,
48%); MS: m/e=275.5 (M+H.sup.+).
[0402] Step B: [1-(2-Methylsulfanyl-ethyl)-piperidin-4-yl]-carbamic
acid tert-butyl ester (0.35 g, 1.0 mmol) was dissolved in
HCl/Methanol (2.5M, 4 mL) and stirred for 1.5 h at 40.degree. C.
After evaporation of the solvent and drying under high vacuum,
1-(2-methylsulfanyl-ethyl)-piperidin-4-ylamine dihydrochloride was
obtained as an off-white solid (0.22 g, 100%); MS: m/e=175.5
(M+H.sup.+).
[0403] Step C: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate,
1-(2-methylsulfanyl-ethyl)-piperidin-4-ylamine dihydrochloride and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=476.7
(M+H.sup.+)
Example 49
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((endo)-9-methyl-9-aza-bicyclo-
[3.3.1]non-3-yl)-urea
[0404] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=456.7
(M+H.sup.+).
Example 50
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-(9-methyl-9-aza-bicycl-
o[3.3.1]non-3-yl)-urea
[0405] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=486.7 (M+H.sup.+)
Example 51
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methylsulfanyl-
-ethyl)-piperidin-4-yl]-urea
[0406] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2-methylsulfanyl-ethyl)-piperidin-4-ylamine
dihydrochloride and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=506.8 (M+H.sup.+).
Example 52
rac-1-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro--
propionyl)-piperidin-4-yl]-urea
[0407] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(4-amino-piperidin-1-yl)-3,3,3-trifluoro-propan-1-one
hydrochloride and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=542.8 (M+H.sup.+).
Example 53
rac-1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-quin-
olin-6-yl]-urea
[0408] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-cyclopropyl-piperidin-4-ylamine and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=472.8 (M+H.sup.+).
Example 54
rac-1-(1,1-Dioxo-hexahydro-thiopyran-4-yl)-3-[2-(8-methoxy-1,2,3,4-tetrahy-
dro-naphthalen-1-ylamino)-quinolin-6-yl]-urea
[0409] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1,1-dioxo-hexahydro-thiopyran-4-ylamine (CAS no.
210240-20-3) and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=495.4 (M+H.sup.+).
Example 55
rac-1-(1-Cyclopropyl-piperidin-4-yl)-3-[2-(8-methoxy-1,2,3,4-tetrahydro-na-
phthalen-1-ylamino)-quinolin-6-yl]-urea
[0410] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 4-amino-1-cyclopropylpiperidine (CAS no. 62813-02-9) and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine MS: m/e=486.1 (M+H.sup.+).
Example 56
rac-1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl-
]-3-endo-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-urea
[0411] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, endo-9-methyl-azabicyclo[3.3.1]-nonan-3-amine and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=500.3 (M+H.sup.+).
Example 57
rac-1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl-
]-3-(1-methyl-piperidin-4-yl)-urea
[0412] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 4-amino-1-methylylpiperidine and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=460.5 (M+H.sup.+).
Example 58
rac-1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-3-[2-(8-methoxy-1,2,3,4-tetrahy-
dro-naphthalen-1-ylamino)-quinolin-6-yl]-urea
[0413] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2-methoxy-ethyl)-piperidin-4-ylamine and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=504.5 (M+H.sup.+).
Example 59
rac-1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-(8-methoxy-1,2,3,4-tetrahyd-
ro-naphthalen-1-ylamino)-quinolin-6-yl]-urea
[0414] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2-fluoroethyl)-piperidin-4-ylamine and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=492.5 (M+H.sup.+).
Example 60
rac-endo-1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-
-6-yl]-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-urea
[0415] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, endo-8-methyl-8-azabicyclo[3.2.1]-octan-3-amine and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=486.5 (M+H.sup.+).
Example 61
1-[1-(2-Fluoro-acetyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinolin-
-6-yl]-urea
[0416] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(4-amino-piperidin-1-yl)-2-fluoro-ethanone
hydrochloride and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine;
MS: m/e=462.6 (M+H.sup.+).
Example 62
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-propionyl)-
-piperidin-4-yl]-urea
[0417] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(4-amino-piperidin-1-yl)-3,3,3-trifluoro-propan-1-one
hydrochloride and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine;
MS: m/e=512.6 (M+H.sup.+).
Example 63
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(3,3,3-trifluoro-propyl)-pi-
peridin-4-yl]-urea
[0418] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(4-amino-piperidin-1-yl)-3,3,3-trifluoro-propan
hydrochloride and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine;
MS: m/e=498.6 (M+H.sup.+).
Example 64
1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-3--
((S)-1-methyl-pyrrolidin-3-yl)-urea
[0419] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, (3S)-1-methyl-3-pyrrolidinamine (CAS no. 214357-95-6)
and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=446.2 (M+H.sup.+).
Example 65
rac-1-[2-(4,6-Dichloro-7-methoxy-indan-1-ylamino)-quinolin-6-yl]-3-isoprop-
yl-urea
[0420] Step A: Rac-7-methoxy-indan-1-ylamine hydrochloride (2.20 g,
0.01 1 mmol) was dissolved in acetic acid (100 mL). After cooling
to 0.degree. C. sulfuryl chloride (1.88 mL, 0.23 mmol) was slowly
added and the reaction mixture was stirred for 16 h at ambient
temperature. Then the solvent was evaporated and the residue was
taken up in isopropanol. Thereby a precipitate formed which was
isolated and dried on high vacuum to yield
rac-4,6-dichloro-7-methoxy-indan-1-ylamine (2.0 g, 68%) as a white
solid; MS: m/e=269.6 (M+H.sup.+).
[0421] Step B:
Rac-(4,6-dichloro-7-methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
was obtained according to the method described in step A of general
example 2; MS: m/e=405.5 (M+H.sup.+).
[0422] Step C:
Rac-(4,6-dichloro-7-methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
(250 mg, 0.62 mmol) were taken up in a mixture of ethanol (5 mL)
and water (2.5 mL). After the addition of ammonium chloride (17 mg,
0.31 mmol) and iron powder (173 mg, 3.1 mmol) the reaction mixture
was heated tom reflux for 6 h. After cooling to ambient temperature
the reaction mixture was filtered through Dicalit.RTM., the
filtrate was concentrated and the residue was subjected to column
chromatography (silica gel, heptane ethyl acetate gradient
9:1.fwdarw.1:1).
Rac-N.sup.2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine
was obtained as a yellow oil (0.11 g, 45%); MS: m/e=375.4
(M+H.sup.+).
[0423] Step D: The title compound was prepared in accordance with
the general method described in example 3 from isopropyl isocyanate
and
rac-N.sup.2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine;
MS: m/e=460.6 (M+H.sup.+).
Example 66
N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N,N-dimethylsulf-
amide
[0424] (R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18
mmol) was dissolved in pyridine (1 mL). Dimethylsulfamoyl chloride
(0.02 mL) was added and stirred for 72 h at ambient temperature.
Then water was added and the mixture extracted with ethyl acetate.
The combined organic phases were dried over sodium sulfate,
filtered and evaporated. The residue was subjected to column
chromatography (silica gel, heptane, ethyl acetate 4:1/1:1) to
yield the title compound as a brown oil (30 mg, 43%); MS: m/e=383.6
(M+H.sup.+).
Example 67
rac-N'-[2-(2,3-dihydro-1-benzofuran-3-ylamino)quinolin-6-yl]-N,N-dimethyls-
ulfamide
[0425] The title compound was prepared in accordance with the
general method described in example 66 from
dimethylsulfamoylchloride and
rac-N.sup.2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine;
MS: m/e=385.6 (M+H.sup.+).
Example 68
rac-N'-{2-[(7-methoxy-2,3-dihydro-1H-inden-1-yl)amino]quinolin-6-yl}-N,N-d-
imethylsulfamide
[0426] The title compound was prepared in accordance with the
general method described in example 66 from dimethylsulfamoyl
chloride and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=412.6 (M+H.sup.+).
Example 69
rac-N'-{2-[(8-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)amino]quinolin-6-y-
l}-N,N-dimethylsulfamide
[0427] The title compound was prepared in accordance with the
general method described in example 66 from dimethylsulfamoyl
chloride and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=427.3 (M+H.sup.+).
Example 70
rac-N'-{2-[(4,6-Dichloro-7-methoxy-2,3-dihydro-1H-inden-1-yl)amino]quinoli-
n-6-yl}-N,N-dimethylsulfamide
[0428] The title compound was prepared in accordance with the
general method described in example 66 from
dimethylsulfamoylchloride and
rac-N.sup.2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine;
MS: m/e=482.6 (M+H.sup.+).
Example 71
tert-butyl
[({2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}amino)s-
ulfonyl]carbamate
[0429] (R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine (0.09 g, 0.33
mmol) and dimethylamino pyridinium N-tert butoxycarbonyl sulfamide
(0.12 g, 0.36 mmol) were dissolved in acetonitrile (2.0 mL). After
addition of triethylamine (0.05 mL, 0.36 mmol) the reaction mixture
was heated to reflux for 16 h. The solvent was removed and the
residue subjected to column chromatography (silica gel,
heptane/ethyl acetate=9:1/4:1/1:1). The title compound was obtained
as a yellow solid (15 mg; 10%); MS: m/e=455.7 (M+H.sup.+).
Example 72
N-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}sulfamide
hydrochloride
[0430] tert-butyl
[({2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}amino)sulfonyl]ca-
rbamate (0.012 mg, 0.026 mmol) was dissolved in HCl/methanol (2.5
M, 1.0 mL) and stirred for 2 h at 60.degree. C. Upon evaporation of
the solvent and drying on high vacuum the title compound was
obtained as a yellow solid (8 mg; 80%); MS: m/e=392.0
(M+H.sup.+).
Example 73
Pyrrolidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0431] The title compound was prepared in accordance with the
general method described in example 66 from pyrrolidine-1-sulfonyl
chloride and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS:
m/e=409.6 (M+H.sup.+).
Example 74
3,3-Difluoro-pyrrolidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0432] The title compound was prepared in accordance with the
general method described in example 66 from
3,3-difluoro-pyrrolidine-1-sulfamoylchloride and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=445.8
(M+H.sup.+).
Example 75
(2-Methoxy-ethyl)-methyl-sulfonic acid
[2-((R)-indan-1-ylamino)quinolin-6-yl]-amide
[0433] The title compound was prepared in accordance with the
general method described in example 66 from
(2-methoxy-ethyl)-methyl-sulfamoyl chloride and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=427.6
(M+H.sup.+).
Example 76
Morpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0434] Step A: 3-(1H-Imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate (1.5 g, 3.0 mmol) was dissolved in
acetonitrile (15 mL) and treated with morpholine (0.30 mL, 4.0
mmol) and stirred for 16 h at ambient temperature. The solvent was
removed and the residue subjected to column chromatography (silica
gel, heptane, ethyl acetate 1:1, 0:1) to yield
4-(imidazole-1-sulfonyl)-morpholine (0.62 g, 83%)as a white solid;
MS: m/e=218.5 (M+H.sup.+).
[0435] Step B: 4-(Imidazole-1-sulfonyl)-morpholine (0.30 g, 1.38
mmol) were dissolved in methylene chloride (6 mL) and methyl
triflate (0.172 mL, 1.5 mmol) was added dropwise at 0.degree.
C.
[0436] After stirring for 2 h at 0.degree. C. a white precipitate
formed which was isolated and dried under high vacuum to yield
1-methyl-3-(morpholine-4-sulfonyl)-3H-imidazol-1-ium
trifluoromethanesulfonate (0.52 g, 99 %); MS: m/e=232.5
(M.sup.+).
[0437] Step C: 1-Methyl-3-(morpholine-4-sulfonyl)-3H-imidazol-1-ium
trifluoromethanesulfonate (0.139 g, 0.36 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (0.10 g, 0.36 mmol)
were dissolved in acetonitrile (2 ML) and stirred for 16 h at
80.degree. C. The solvent was removed and the residue subjected to
column chromatography (silica gel, heptane, ethyl acetate 4:1/1:1)
to yield morpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide (0.07 g, 45%) as a
yellow solid; MS: m/e=425.7 (M+H.sup.+).
Example 77
4-Methyl-piperazine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0438] The title compound was prepared in accordance with the
general method described in example 66 from
4-methyl-piperazine-1-sulfonyl chloride and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=438.8
(M+H.sup.+).
Example 78
Thiomorpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0439] Step A: 4-(Imidazole-1-sulfonyl)-thiomorpholine was prepared
in accordance with step A of the general method described in
example 76 from thiomorpholine and
3-(1H-Imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=234.8 (M+H.sup.+). Step B:
1-Methyl-3-(thiomorpholine-4-sulfonyl)-3H-imidazol-1-ium
trifluoromethanesulfonate was prepared in accordance with step B of
the general method described in example 76 from
4-(imidazole-1-sulfonyl)-thiomorpholine and methyl triflate; MS:
m/e=248.9 (M.sup.+). Step C: The title compound was prepared in
accordance with step C of the general method described in example
76 from 1-methyl-3-(thiomorpholine-4-sulfonyl)-3H-imidazol-1-ium
trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=441.8
(M+H.sup.+).
Example 79
1,1-Dioxo-thiomorpholine-4-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0440] The title compound was prepared in accordance with the
general method described in example 66 from
1,1-dioxo-thiomorpholine-4-sulfonyl chloride and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=473.7
(M+H.sup.+).
Example 80
N-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N'-(tetrahydro-2H-
-pyran-4-yl)sulfamide
[0441] 3-(1H-midazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate (0.394 g, 1.10 mmol) and
4-amino-tetrahydropyran (0.10 g, 1.0 mmol) were dissolved in
acetonitrile (5 mL) and stirred for 30 min at ambient temperature.
Then (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (0.054 g, 0.20
mmol) were added and the reaction mixture was stirred at 80.degree.
C. for 16 h. The solvent was removed and the residue subjected
twice to column chromatography (silica gel, first chromatography
heptane/ethyl acetate 4:1/1:1/2:1; second chromatography
heptane/ethyl acetate 1:1) to yield the title compound (5 mg, 1%)
as a yellow solid; MS: m/e=439.7 (M+H.sup.+).
Example 81
N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N-methyl-N-(tetr-
ahydro-2H-pyran-4-yl)sulfamide
[0442] Step A: Imidazole-1-sulfonic acid
methyl-(tetrahydro-pyran-4-yl)-amide was prepared in accordance
with step A of the general method described in example 76 from
methyl-(tetrahydro-pyran-4-yl)amine hydrochloride and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=246.8 (M+H.sup.+).
[0443] Step B:
1-Methyl-3-[methyl-(tetrahydro-pyran-4-yl)-sulfamoyl]-3(H)-imidazol-1-ium
trifluoromethanesulfonate was prepared in accordance with step B of
the general method described in example 76 from
imidazole-1-sulfonic acid methyl-(tetrahydro-pyran-4-yl)-amide and
methyl triflate; MS: m/e=260.4 (M.sup.-).
[0444] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
1-methyl-3-[methyl-(tetrahydro-pyran-4-yl)-sulfamoyl]-3H-imidazol-1-ium
trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=453.8
(M+H.sup.+).
Example 82
1,4-Dioxa-8-aza-spiro[4.5]decane-8-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0445] Step A:
8-(Imidazole-1-sulfonyl)-1,4-dioxa-8-aza-spiro[4.5]decane was
prepared in accordance with step A of the general method described
in example 76 from 1,4-dioxa-8-azaspiro(4,5)decan and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=274.5 (M+H.sup.+).
[0446] Step B:
3-(1,4-Dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-1-methyl-3(H)-imidazol-1--
ium trifluoromethanesulfonate was prepared in accordance with step
B of the general method described in example 76 from
8-(imidazole-1-sulfonyl)-1,4-dioxa-8-aza-spiro[4.5]decane and
methyl triflate; MS: m/e=288.4 (M.sup.-).
[0447] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
3-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-1-methyl-3(H)-imidazol-1--
ium trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=481.8
(M+H.sup.+).
Example 83
4-Methoxymethyl-piperidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0448] Step A: [1-(Imidazole-1-sulfonyl)-piperidin-4-yl]-methanol
was prepared in accordance with step A of the general method
described in example 76 from 4-(hydroxymethyl)-piperidine and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=246.5 (M+H.sup.+).
[0449] Step B:
3-(4-Methoxymethyl-piperidine-1-sulfonyl)-1-methyl-3(H)-imidazol-1-ium
trifluoromethanesulfonate was prepared in accordance with step B of
the general method described in example 76 from
[1-(imidazole-1-sulfonyl)-piperidin-4-yl]-methanol and methyl
triflate; MS: m/e=274.4 (M.sup.+).
[0450] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
3-(4-methoxymethyl-piperidine-1-sulfonyl)-1-methyl-3(H)-imidazol-1-ium
trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=481.8
(M+H.sup.+).
Example 84
4-Methoxy-piperidine-1-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0451] Step A: 1-(Imidazole-1-sulfonyl)-piperidin-4-ol was prepared
in accordance with step A of the general method described in
example 76 from 4-hydroxypiperidin and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=232.5 (M+H.sup.+).
[0452] Step B:
3-(4-Methoxypiperidine-1-sulfonyl)-1-methyl-3(H)-imidazol-1-ium
trifluoromethanesulfonate was prepared in accordance with step B of
the general method described in example 76 from
1-(imidazole-1-sulfonyl)-piperidin-4-ol and methyl triflate; MS:
m/e=260.4 (M.sup.+).
[0453] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
3-(4-methoxypiperidine-1-sulfonyl)-1-methyl-3(H)-imidazol-1-ium
trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=453.8
(M+H.sup.+).
Example 85
N-cyclopropyl-N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}-N--
methylsulfamide
[0454] Step A: Imidazole-1-sulfonic acid cyclopropyl-methyl-amide
was prepared in accordance with step A of the general method
described in example 76 from cyclopropyl-methylamine and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=202.5 (M+H.sup.+).
[0455] Step B:
3-(Cyclopropyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium
trifluoromethane-sulfonate was prepared in accordance with step B
of the general method described in example 76 from
imidazole-1-sulfonic acid cyclopropyl-methyl-amide and methyl
triflate; MS: m/e=216.4 (M.sup.+).
[0456] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
3-(cyclopropyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium
trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=409.7
(M+H.sup.+).
Example 86
N-(cyclopropylmethyl)-N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin--
6-yl}-N-methylsulfamide
[0457] Step A: Imidazole-1-sulfonic acid
cyclopropylmethyl-methyl-amide was prepared in accordance with step
A of the general method described in example 76 from
cyclopropylmethyl-methylamine and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=216.5 (M+H.sup.+).
[0458] Step B:
3-(Cyclopropylmethyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium
trifluoromethanesulfonate was prepared in accordance with step B of
the general method described in example 76 from
imidazole-1-sulfonic acid cyclopropylmethyl-methyl-amide and methyl
triflate; MS: m/e=230.4 (M.sup.-).
[0459] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
3-(cyclopropylmethyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium
trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=423.7
(M+H.sup.+).
Example 87
2-Oxa-8-aza-spiro[4.5]decane-8-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]amide
[0460] Step A:
8-(Imidazole-1-sulfonyl)-2-oxa-8-aza-spiro[4.5]decane was prepared
in accordance with step A of the general method described in
example 76 from 2-oxa-8-aza-spiro[4.5]decane hydrochloride and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=216.5 (M+H.sup.+).
[0461] Step B:
1-Methyl-3-(2-oxa-8-aza-spiro[4.5]decane-8-sulfonyl)-3(H)-imidazol-1-ium
trifluoromethane-sulfonate was prepared in accordance with step B
of the general method described in example 76 from
8-(imidazole-1-sulfonyl)-2-oxa-8-aza-spiro[4.5]decane and methyl
triflate; MS: m/e=286.4 (M.sup.+).
[0462] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
1-methyl-3-(2-oxa-8-aza-spiro[4.5]decane-8-sulfonyl)-3(H)-imidazol-1-ium
trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=479.7
(M+H.sup.+).
Example 88
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0463] Step A:
(1S,4S)-5-(Imidazole-1-sulfonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane
was prepared in accordance with step A of the general method
described in example 76 from
all-(S)-(+)-2-oxa-5-aza-bicyclo[2.2.1]heptane hydrochloride and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=230.5 (M+H.sup.-).
[0464] Step B:
1-Methyl-3-[(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)sulfonyl]-3(H)-i-
midazol-1-ium trifluoromethane-sulfonate was prepared in accordance
with step B of the general method described in example 76 from
(1S,4S)-5-(imidazole-1-sulfonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane
and methyl triflate; MS: m/e=244.4 (M.sup.+).
[0465] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
1-methyl-3-[(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)sulfonyl]-3(H)-i-
midazol-1-ium trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=437.7
(M+H.sup.+).
Example 89
(1S,5R)-8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0466] Step A:
3-(Imidazole-1-sulfonyl)-8-oxa-3-aza-bicyclo[3.2.1]octane was
prepared in accordance with step A of the general method described
in example 76 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride and
3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium
trifluoromethanesulfonate; MS: m/e=244.4 (M+H.sup.+).
[0467] Step B:
1-Methyl-3-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-3(H)-imidazol-1--
ium trifluoromethanesulfonate was prepared in accordance with step
B of the general method described in example 76 from
3-(imidazole-1-sulfonyl)-8-oxa-3-aza-bicyclo[3.2.1]octane and
methyl triflate; MS: m/e=258.4 (M.sup.-).
[0468] Step C: The title compound was prepared in accordance with
step C of the general method described in example 76 from
1-methyl-3-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-3(H)-imidazol-1--
ium trifluoromethanesulfonate and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=451.7
(M+H.sup.+).
Example 90
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-amide
[0469] The title compound was prepared in accordance with step C of
the general method described in example 76 from
N.sup.2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine and
1-methyl-3-[(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)sulfonyl]-3(H)-i-
midazol-1-ium trifluoromethanesulfonate; MS: m/e=439.7
(M+H.sup.+).
Example 91
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-ami-
de
[0470] The title compound was prepared in accordance with step C of
the general method described in example 76 from
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine and
1-methyl-3-[(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)sulfonyl]-3(H)-i-
midazol-1-ium trifluoromethanesulfonate; MS: m/e=481.0
(M+H.sup.+).
Example 92
N-Cyclopropyl-N'-{2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]quinolin-6-yl}sul-
famide
[0471] The title compound was prepared in accordance with the
general method described in example 66 from
cyclopropylsulfamoylchloride and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=395.6
(M+H.sup.+).
Example 93
rac-1-Isopropyl-3-[2-(7-methoxy-4-methyl-indan-1-ylamino)-quinolin-6-yl]-u-
rea
[0472] Step A: 7-Methoxy-4-Methyl-1-indanon (1.0 g, 0.006 mol) was
dissolved in ethanol (10 mL) and hydroxylamine hydrochloride (0.8
g, 0.012 mol) and sodium acetate (0.96 g, 0.012 mmol) were added.
The reaction mixture was heated to reflux for 3 h. Then water (10
mL) was added and a precipitation formed which was filtered. The
precipitate was washed with water, isolated and dried under high
vacuum to yield 7-methoxy-4-methyl-indan-1-one oxime (1.0 g, 92%)
as a white solid; MS: m/e=192.4 (M+H.sup.+).
[0473] Step B: Crude 7-methoxy-4-methyl-indan-1-one oxime (1.0 g,
0.005 mmol) from the procedure described above was dissolved in
methanol/HCl (10 mL, 2 M). palladium on carbon 10% (100 mg) was
added and the compound was hydrogenated under an atmosphere of
hydrogen (3 bar) at 70.degree. C. for 2 h. After filtration,
evaporation of the solvent and drying under high vacuum crude
rac-7-methoxy-4-methyl-indan-1-ylamine hydrochloride (1 g, 89%) was
obtained as a white solid and used in the next reaction without
further purification; MS: m/e=214.9 (M+H.sup.+).
[0474] Step C:
Rac-(7-Methoxy-4-methyl-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
was obtained from crude rac-7-methoxy-4-methyl-indan-1-ylamine
hydrochloride and 2-chloro-6-nitro-quinoline according to the
general procedure described in step A of example 2; MS: m/e=350.6
(M+H.sup.+)
[0475] Step D:
Rac-N.sup.2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine
was obtained from
(7-methoxy-4-methyl-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
according to the general procedure described in step B of example
2; MS: m/e=320.6 (M+H.sup.+). Step E: The title compound was
prepared in accordance with the general method described in example
3 from
rac-N.sup.2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine
and isopropyl isocyanate; MS: m/e=405.6 (M+H.sup.+).
Example 94
rac-N'-{2-[(7-Methoxy-4-methyl-2,3-dihydro-1H-inden-1-yl)amino]quinolin-6--
yl}-N,N-dimethylsulfamide
[0476] The title compound was prepared in accordance with the
general method described in example 66 from
dimethylsulfamoylchloride and
rac-N.sup.2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine;
MS: m/e=427.6 (M+H.sup.+).
Example 95
rac-1-[2-(7-Methoxy-4-methyl-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-p-
iperidin-4-yl)-urea
[0477] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-methyl-piperidin-4-ylamine and
rac-N.sup.2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine;
MS: m/e=460.8 (M+H.sup.+).
Example 96
4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidine-1-carboxyl-
ic acid methyl ester
[0478] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 4-amino-piperidine-1-carboxylic acid methyl ester
hydrochloride and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine;
MS: m/e=460.8 (M+H.sup.-).
Example 97
1-[1-(2-Fluoro-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinolin--
6-yl]-urea
[0479] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2-fluoro-ethyl)-piperidin-4-ylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=448.8
(M+H.sup.+).
Example 98
rac-1-[2-(4,6-dichloro-7-methoxy-indan-1-ylamino)-quinolin-6-yl]-3-(1-meth-
yl-piperidin-4-yl)-urea
[0480] Step A: Rac-7-Methoxy-indan-1-ylamine (2.2 g, 0.011 mol)
were dissolved in acetic acid. Over 10 min sulfuryl chloride (1.9
mL, 0.023 mol) was added dropwise at 0.degree. C. The reaction
mixture was stirred over night at ambient temperature. Then the
solvent was removed and the residue was taken up in iso-propanol.
After stirring for some time a precipitation formed which was
isolated and dried under high vacuum.
Rac-4,6-dichloro-7-methoxy-indan-1-ylamine (2.0 g, 68%) was
obtained as a white solid; MS: m/e=232.4 (M+H.sup.+).
[0481] Step B:
Rac-(4,6-dichloro-7-methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
was obtained from rac-4,6-dichloro-7-methoxy-indan-1-ylamine and
2-chloro-6-nitro-quinoline according to the general procedure
described in step A of example 2; MS: m/e=405.6 (M+H.sup.+).
[0482] Step C:
Rac-N.sup.2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine
was obtained from
rac-(4,6-dichloro-7-methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
according to the general procedure described in step B of example
2; MS: m/e=375.5 (M+H.sup.+).
[0483] Step D: The title compound was prepared in accordance with
the general method 4 described in example 16 from
rac-N.sup.2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine,
bis(trichloromethyl) carbonate and 1-methyl-piperidin-4-ylamine;
MS: m/e=515.7 (M+H.sup.+).
Example 99
1-((3-exo)-8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-((R)-indan-1-y-
lamino)-quinolin-6-yl]-urea
[0484] Step A: 8-Cyclopropyl-8-aza-bicyclo[3.2.1]octan-3-one oxime:
A mixture of 8-cyclopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS no:
60206-33-9) (17.86 g, 108.08 mmol) in ethanol (500 mL) with
pyridine (13.05 mL, 162.1 mmol) and hydroxylamine hydrochloride
(9.764 g, 140.51 mmol) was refluxed overnight. Cooled to 23.degree.
C., filtered off, washed with ethanol and ether and dried in vacuum
to give a white solid, which was suspended in 200 mL sat.
Na.sub.2CO.sub.3 solution and extracted 3 times with
dichloromethane, the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered off and evaporated totally, dried in
high vacuum to give the title compound as white crystals (16.3 g,
84%); MS: m/e=181.2 (M+H.sup.+).
[0485] Step B:
(3-exo)-8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-ylamine
dihydrochloride: A solution of the above described
8-cyclopropyl-8-aza-bicyclo[3.2.1]octan-3-one oxime (2 g, 11.09
mmol) in pentanol (50 mL) was heated under reflux (150.degree. C.).
Sodium (3.089 g, 134.356 mmol) was added portionwise over 2 h. The
reaction was then heated under reflux for further 2 h, then cooled
to 0.degree. C. Water was added until no more hydrogen gas was
evolved. The mixture was acidified using 6 N hydrochloride
solution. The phases were separated, extracted the organic layer
twice with 6 N hydrochloride solution. The combined aqueos extracts
were made alkaline in an ice bath with NaOH pellets to achieve pH
12. Extracted 3 times with dichloromethane, dried the combined
organic layers over Na.sub.2SO.sub.4, filtered off and evaporated
totally to give a light yellow oil (5 g contains pentanol).
Dissolved in 20 mL ethanol and added trimethylchlorosilane (8.42
mL, 66.57 mmol), then added 150 mL diethyl ether and stirred
overnight. Filtered the solid off and dried in high vaccum to give
the title compound as white crystals (2.1 g, 79.1%); MS: m/e=167.2
(M+H.sup.+).
[0486] Step C: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate (44 mg, 0.163 mmol), the above
described (3-exo)-8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-ylamine
dihydrochloride (87 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as a white solid (40 mg, 21%); MS: m/e=468.3
(M+H.sup.-).
Example 100
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[(3-exo)-9-(2,2,2-trifluoro-et-
hyl)-9-aza-bicyclo[3.3.1]non-3-yl]-urea
[0487] Step A:
9-(2,2,2-Trifluoro-ethyl)-9-aza-bicyclo[3.3.1]nonan-3-one oxime: A
mixture of
9-(2,2,2-trifluoro-ethyl)-9-aza-bicyclo[3.3.1]nonan-3-one (CAS no:
209054-63-7) (6.70 g, 30 mmol) in ethanol (100 mL) and
hydroxylamine hydrochloride (2.23 g, 32 mmol) was refluxed for 6 h.
The reaction mixture was evaporated totally, the residue extracted
with dichloromethane and sodium carbonate solution, the organic
layers dried over Na.sub.2SO.sub.4, filtered and the solvents
evaporated to give the title compound as a light brown solid. (6.4
g, 89%); MS: m/e=237.1 (M+H.sup.+).
[0488] Step B:
(3-exo)-9-(2,2,2-Trifluoro-ethyl)-9-aza-bicyclo[3.3.1]non-3-ylamine
dihydrochloride: A solution of the above described
9-(2,2,2-trifluoro-ethyl)-9-aza-bicyclo[3.3.1]nonan-3-one oxime
(1.89 g, 8 mmol) was treated with sodium in pentanol, followed by
aqueous workup and HCl salt generation as described in Example 99
Step B. Obtained the title compound as white crystals (1.64 g,
69%); MS: m/e=223.1 (M+H.sup.+).
[0489] Step C: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate (49 mg, 0.17 mmol), the above
described (3-exo)-9-(2,2,2-trifluoro-ethyl)-9-aza-bicyclo [3.3.1
]non-3-ylamine dihydrochloride (107 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as an off-white foam (120 mg, 63%); MS: m/e=524.2
(M+H.sup.+).
Example 101
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-8-methyl-8-aza-bicycl-
o[3.2.1]oct-3-yl)-urea
[0490] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate (49 mg, 0.17 mmol), the
(3-exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine dihydrochloride
(CAS no: 340682-25-9) (78 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as an off-white solid (82 mg, 51%); MS: m/e=442.4
(M+H.sup.+).
Example 102
rac-N.sup.2-(7-Methyl-indan-1-yl)-quinoline-2,6-diamine
[0491] The title compound was prepared in accordance with the
general method described in example 2 from
2-chloro-6-nitro-quinoline and rac-7-methyl-indan-1-ylamine (CAS
no: 168902-78-1); MS: m/e=290.4 (M+H.sup.+).
Example 103
rac-1-Isopropyl-3-[2-(7-methyl-indan-1-ylamino)-quinolin-6-yl]-urea
[0492] The title compound was prepared in accordance with the
general method described in example 3 from
rac-N.sup.2-(7-methyl-indan-1-yl)-quinoline-2,6-diamine and
isopropyl isocyanate; MS: m/e=375.4 (M+H.sup.+).
Example 104
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((7-exo)-9-methyl-3-oxa-9-aza--
bicyclo[3.3.1]non-7-yl)-urea
[0493] Step A:
(7-exo)-9-Methyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-ylamine
dihydrochloride: A solution of
9-methyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one oxime (CAS no:
99767-87-0) (0.835 g, 4.0 mmol) was treated with sodium in
pentanol, followed by aqueous workup and HCl salt generation as
described in Example 99 Step B. Obtained the title compound as
brown solid (0.38 g, 34%); MS: m/e=157.1 (M+H.sup.+).
[0494] Step B: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate (49 mg, 0.17 mmol), the above
described (7-exo)-9-methyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-ylamine
dihydrochloride (107 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (83 mg, 0.363 mmol);
obtained as a light brown solid (56 mg, 34%); MS: m/e=458.5
(M+H.sup.+).
Example 105
1-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl]-3--
((R)-1-methyl-pyrrolidin-3-yl)-urea
[0495] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, (3R)-1-methyl-3-pyrrolidinamine (CAS no: 457097-75-5)
and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine; MS: m/e=446.4 (M+H.sup.+).
Example 106
rac-N.sup.2-(5-Fluoro-indan-1-yl)-quinoline-2,6-diamine
[0496] The title compound was prepared in accordance with the
general method described in example 2 from
2-chloro-6-nitro-quinoline and rac-5-fluoro-indan-1-ylamine (CAS
no: 148960-33-2); MS: m/e=294.3 (M+H.sup.+).
Example 107
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea
[0497] The title compound was prepared in accordance with the
general method described in example 3 from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and
isopropyl isocyanate; MS: m/e=379.4 (M+H.sup.+).
Example 108
{2-[2-((R)-Indan-1-ylamino)-quinolin-6-ylamino]-ethyl}-methyl-carbamic
acid tert-butyl ester
[0498] A mixture of (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine
(453 mg, 1.645 mmol) in Methanol (10 mL) with acetic acid (0.3 mL,
4.935 mmol) and commercially available methyl-(2-oxo-ethyl)carbamic
acid tert-butyl ester (300 mg, 1.731 mmol) was stirred at
23.degree. C. for 1 h. Portionwise addition of sodium
cyanoborohydride (286 mg, 4.11 mmol) was followed by additional
stirring at 23.degree. C. for 3 h. Poured onto saturated
NaHCO.sub.3-solution and extracted twice with ethyl acetate, dried
over Na.sub.2SO.sub.4 and evaporated totally gave a crude product
which was purified by flash chromatography with heptane and ethyl
acetate to give the title compound as a yellow foam (550 mg, 73%);
MS: m/e=433.4 (M+H.sup.+).
Example 109
N.sup.2--(R)-Indan-1-yl-N-6-(2-methylamino-ethyl)-quinoline-2,6-diamine
[0499] A solution of
{2-[2-((R)-Indan-1-ylamino)-quinolin-6-ylamino]-ethyl}-methyl-carbamic
acid tert-butyl ester (Example 108) (0.5 g, 1.156 mmol) in
dichloromethane (5 mL) was cooled to 0.degree. C. trifluoroacetic
acid (2 mL) was dropwise added, the cooling bath was and removed
the and the mixture was stirred at 23.degree. C. for 2 h. Poured
into saturated NaHCO.sub.3-solution and extracted twice with
dichloromethane, dried over Na.sub.2SO.sub.4, filtered off and
evaporated totally to yield a crude product which was purified by
flash chromatography with heptane/ethyl acetate to give the title
compound as a light brown oil (220 mg, 57%); MS: m/e=333.4
(M+H.sup.-).
Example 110
1-((3-exo)-9-Cyclopropyl-9-aza-bicyclo[3.3.1]non-3-yl)-3-[2-((R)-indan-1-y-
lamino)-quinolin-6-yl]-urea
[0500] Step A: 9-Cyclopropyl-9-aza-bicyclo[3.3.1]nonan-3-one:
Glutaraldehyde (36.5 mL, 95 mmol) and 1,3-acetonedicarboxylic acid
(10 g, 65 mmol) were suspended in water (100 mL) and stirred by a
mechanical stirrer under argon for 30 min. To the yellow solution
cyclopropylamine (3.5 mL, 50 mmol) were added in one portion
whereby a slightly exothermic reaction occured and a gas evolved.
The reaction mixture was stirred at 23.degree. C. overnight. The
reaction mixture was acidified with 3 N Hydrochloride solution
until pH<2, then extracted with dichloromethane. The water layer
was now adjusted with 3 N NaOH to pH 8 and extracted three times
with dichloromethane, the organic layers were combined, dried over
MgSO.sub.4, filtered and the solvents were evaporated. Purification
of the crude product by flash chromatography with n-heptane and
ethyl acetate gave the title compound as a white solid (940 mg,
11%); MS: m/e=180.2 (M+H.sup.+).
[0501] Step B: 9-Cyclopropyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime:
A mixture of the above described
9-cyclopropyl-9-aza-bicyclo[3.3.1]nonan-3-one (890 mg, 5.0 mmol) in
ethanol (20 mL) and hydroxylamine hydrochloride (366 mg, 5.3 mmol)
was refluxed for 6 h. The reaction mixture was evaporated totally,
the residue extracted with ethyl acetate and sodium bicarbonate
solution, the organic layers dried over Na.sub.2SO.sub.4, filtered
and the solvents evaporated to give the title compound as a white
solid. (890 mg, 100%); MS: m/e=195.2 (M+H.sup.+).
[0502] Step C:
(3-exo)-9-Cyclopropyl-9-aza-bicyclo[3.3.1]non-3-ylamine
dihydrochloride: A solution of the above described
9-cyclopropyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime (850 mg, 4.4
mmol) was treated with sodium in pentanol, followed by aqueous
workup and HCl salt generation as described in Example 99 Step B.
Obtained the title compound as white crystals (820 mg, 74%); MS:
m/e=181.1 (M+H.sup.+).
[0503] Step D: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate (49 mg, 0.17 mmol), the above
described (3-exo)-9-cyclopropyl-9-aza-bicyclo[3.3.1]non-3-ylamine
dihydrochloride (92 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as an off-white solid (60 mg, 31%); MS: m/e=482.3
(M+H.sup.-).
Example 111
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((7-exo)-9-methyl-3-thia-9-aza-
-bicyclo[3.3.1]non-7-yl)-urea
[0504] Step A: 9-Methyl-3-thia-9-aza-bicyclo[3.3.1]nonan-7-one
oxime: A mixture of 9-Methyl-3-thia-9-aza-bicyclo[3.3.1]nonan-7-one
(CAS no: 99709-31-6) (3.0 g, 17.5 mmol) in ethanol (100 mL) and
hydroxylamine hydrochloride (1.58 g, 22.8 mmol) was refluxed for 16
h. Cooled to 23.degree. C., the precipitate was filtered off,
washed with ethanol and diethyl ether and dried in vaccum to give a
light brown solid (2.5 g), which was partitioned between
dichloromethane and sodium carbonate solution, the organic layers
dried over Na.sub.2SO.sub.4, filtered and the solvents evaporated
to give the title compound as a white solid. (1.3 g, 40%); MS:
m/e=187.1 (M+H.sup.+).
[0505] Step B:
(7-exo)-9-Methyl-3-thia-9-aza-bicyclo[3.3.1]non-7-ylamine
dihydrochloride: A solution of the above described
9-methyl-3-thia-9-aza-bicyclo[3.3.1]nonan-7-one oxime (1.55 g, 8.32
mmol) was treated with sodium in pentanol, followed by aqueous
workup and HCl salt generation as described in Example 99 Step B.
Obtained the title compound as white crystals (1.6 g, 78%); MS:
m/e=173.1 (M+H.sup.+).
[0506] Step C: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate (44 mg, 0.16 mmol), the above
described (7-exo)-9-methyl-3-thia-9-aza-bicyclo[3.3.1]non-7-ylamine
dihydrochloride (89 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as an off-white solid (20 mg, 12%); MS: m/e=474.3
(M+H.sup.-).
Example 112
4-Isopropyl-piperazine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0507] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate (44 mg, 0.16 mmol), commercially available
1-(2-propyl)-piperazine (47 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as a white solid (32 mg, 21%); MS: m/e=430.4
(M+H.sup.+).
Example 113
4-tert-Butyl-piperazine-1-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0508] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate (44 mg, 0.16 mmol), commercially available
N-tert-butylpiperazine (52 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as a white solid (150 mg, 93%); MS: m/e=444.5
(M+H.sup.+).
Example 114
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-methyl-imidazolidin-2-one
[0509] To a solution of
N.sup.2--(R)-indan-1-yl-N.sup.6-(2-methylamino-ethyl)-quinoline-2,6-diami-
ne (Example 109) (200 mg, 0.6 mmol) in dichloromethane (100 mL) at
0.degree. C. was added 1,1'-carbonyldiimidazole (98 mg, 0.6 mmol)
the icebath was removed and the mixture was stirred at 23.degree.
C. overnight, then 2 h at 50.degree. C. All volatiles were removed
in vacuum and the residue was purified by basic silica gel column
chromatography with heptane to ethyl acetate to give the title
compounds as a light brown solid (35 mg, 16%); MS: m/e=359.2
(M+H.sup.+).
Example 115
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperidi-
n-4-yl)-urea
[0510] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no: 127285-08-9)
and rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine; MS:
m/e=460.6 (M-H.sup.+).
Example 116
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-isobutyramide
[0511] (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (0.05 g,
0.18mmol), triethylamine (0.028 mL, 0.2 mmol) and isobutyryl
chloride (0.021 mL, 0.2 mmol) were dissolved in toluene (2.0
mL).
[0512] The reaction mixture was heated to 80.degree. C. A
precipitation formed. The reaction mixture was diluted with water
and extracted with dichloromethane (3.times.). The combined organic
phases were dried over sodium sulfate and evaporated. The crude
product was purified by column chromatography (silica gel,
heptane:ethyl acetate 9:1/4:1/2:1/1:1). The title compound (0.049
g, 78%) was obtained as a yellow solid; MS: m/e=346.6
(M+H.sup.+).
Example 117
2-Cyclopentyl-N-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-acetamide
[0513] The title compound was prepared in accordance with the
general method 9 described in example 116 from cyclopentylacetyl
chloride, triethylamine and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=386.7
(M+H.sup.+).
Example 118
rac-N-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl-
]-isobutyramide
[0514] The title compound was prepared in accordance with the
general method 9 described in example 116 from isobutyryl chloride,
triethylamine and
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline--
2,6-diamine; MS: m/e=390.3 (M+H.sup.+).
Example 119
rac-2-Dimethylamino-N-[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamin-
o)-quinolin-6-yl]-acetamide
[0515] N,N-Dimethylglycine (49 mg, 0.48 mmol), N,N-diisopropyl
ethyl amine (217 mg, 1.68 mmol) and
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (220 mg, 0.69 mmol) were dissolved in
dichloromethane (6 mL) and dimethylformamide (1.5 mL). The reaction
mixture was stirred at room temperature for 30 minutes.
rac-N.sup.2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine (150 mg, 0.47 mmol) was added and stirred was continued
overnight. The reaction mixture was diluted with water and
extracted with dichloromethane (3.times.). The combined organic
phases were dried over sodium sulfate and evaporated. The crude
product was purified by column chromatography (silica gel,
dichloromethane/methanol 100:0.fwdarw.90:10). The title compound
(147 mg, 77%) was obtained as a light brown solid; MS: m/e=405.5
(M+H.sup.+).
Example 120
rac-2-Methoxy-N-[2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-qui-
nolin-6-yl]-acetamide
[0516] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine and methoxyacetic acid; MS: m/e=392.3 (M+H.sup.+).
Example 121
rac-N-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl-
]-2-morpholin-4-yl-acetamide
[0517] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine and morpholin-4-yl-acetic acid; MS: m/e=447.3
(M+H.sup.+).
Example 122
{[2-((R)-Indan-1-ylamino)-quinolin-6-ylcarbamoyl]-methyl}-arbamic
acid tert-butyl ester
[0518] (R)--N.sup.2-Indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18
mmol) were dissolved in tetrahydrofuran (3 mL) and cooled down to
0.degree. C. Then N-(tert-butoxycarbonyl)glycine (0.035 g, 0.2
mmol), 1-hydroxybenzotriazole (0.027 g, 0.2 mmol),
diisopropylethylamine (0.068 mL, 0.4 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038
g, 0.2 mmol) were added. After 30 min at 0.degree. C. the mixture
was allowed to warm up to ambient temperature and was stirred there
for another 16 h. The reaction mixture was diluted with water and
extracted with ethyl acetate (3.times.20 mL). The combined organic
phases were dried on sodium sulfate, filtered, concentrated and the
residue was subjected to column chromatography (silica gel,
heptane/ethyl acetate 9:1, 4:1, 1:1). The title compound was
obtained as a yellow foam (0.066 g, 86%); MS: m/e=433.7
(M+H.sup.+).
Example 123
2-Amino-N-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-acetamide
[0519]
{[2-((R)-Indan-1-ylamino)-quinolin-6-ylcarbamoyl]-methyl}-arbamic
acid tert-butyl ester (0.05 g, 0.12 mmol) were dissolved in
methylene chlorid (1.0 mL). At 0.degree. C. trifluoro acetic acid
(0.085 mL, 1.2 mmol) were added. The reaction mixture was stirred
at ambient temperature for 72 h. Upon addition of sat. sodium
carbonate the mixture was extracted with ethyl acetate (3.times.10
mL). The combined organic phases were dried on sodium sulfate,
filtered and concentrated. After drying under high vacuum the title
compound was obtained as a yellow solid (0.032 g, 83%); MS:
m/e=333.7 (M+H.sup.+).
Example 124
1-Methyl-piperidine-4-carboxylic acid
[2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide
[0520] According to the general method described in example 122 the
title compound was obtained from
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine as an off-white
solid; MS: m/e=333.7 (M+H.sup.+).
Example 125
rac-N-[2-(8-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinolin-6-yl-
]-2-(tetrahydro-pyran-4-yl)-acetamide
[0521] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6--
diamine and tetrahydropyran-4-yl-acetic acid; MS: m/e=446.1
(M+H.sup.+).
Example 126
rac-2-Dimethylamino-N-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-acetam-
ide
[0522] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) and N,N-dimethylglycine; MS: m/e=391.4 (M+H.sup.+).
Example 127
rac-N-[2-(6-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-1-
-yl)-acetamide
[0523] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and
(4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.5
(M+H.sup.+).
Example 128
rac-(N)-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-isobutyramide
[0524] The title compound was prepared in accordance with the
general method 9 described in example 116 from isobutyryl chloride,
triethylamine and
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172); MS: m/e=376.4 (M+H.sup.+).
Example 129
rac-1-Methyl-piperidine-4-carboxylic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide
[0525] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) and 1-methyl-piperidine-4-carboxylic acid; MS: m/e=414.3
(M+H.sup.+).
Example 130
rac-1-Isopropyl-3-[2-(7-methoxy-5-methyl-indan-1-ylamino)-quinolin-6-yl]-u-
rea
[0526] Step A: 7-Methoxy-5-methyl-1-indanon (CAS no: 62358-78-5)
(7.70 g, 0.044 mol) was dissolved in ethanol (40 mL) and
hydroxylamine hydrochloride (6.23 g, 0.09 mol) and sodium acetate
(7.38 g, 0.09 mol) were added. The reaction mixture was heated to
reflux for 3 h. Then water (100 mL) was added and a precipitation
formed which was filtered. The precipitate was washed with water,
isolated and dried under high vacuum to yield
7-methoxy-5-methyl-indan-1-one oxime (8.20 g, 98%) as a white
solid; MS: m/e=192.4 (M+H.sup.+).
[0527] Step B: Crude 7-methoxy-5-methyl-indan-1-one oxime (8.0 g,
0.042 mol) from the procedure described above was dissolved in
methanol/HCl (10 mL, 2 M). palladium on carbon 10% (800 mg) was
added and the compound was hydrogenated under an atmosphere of
hydrogen (3 bar) at 70.degree. C. for 27 h. After filtration,
evaporation of the solvent and drying under high vacuum crude
rac-7-methoxy-5-methyl-indan-1-ylamine hydrochloride (2.3 g, 26%)
was obtained as a white solid and used in the next reaction without
further purification; MS: m/e=214.9 (M+H.sup.+).
[0528] Step C:
Rac-(7-Methoxy-5-methyl-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
was obtained from crude rac-7-methoxy-5-methyl-indan-1-ylamine
hydrochloride and 2-chloro-6-nitro-quinoline according to the
general procedure described in step A of example 2; MS: m/e=350.6
(M+H.sup.+)
[0529] Step D:
Rac-N.sup.2-(7-Methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine
was obtained from
rac-(7-methoxy-5-methyl-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine
according to the general procedure described in step B of example
2; MS: m/e=320.6 (M+H.sup.+).
[0530] Step E: The title compound was prepared in accordance with
the general method described in example 3 from
rac-N.sup.2-(7-methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine
and isopropyl isocyanate; MS: m/e=405.6 (M+H.sup.+).
Example 131
rac-1-[2-(7-Methoxy-5-methyl-indan-1-ylamino)-quinolin-6-yl]-3-(1-methyl-p-
iperidin-4-yl)-urea
[0531] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-methyl-piperidin-4-ylamine and
rac-N.sup.2-(7-methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine;
MS: m/e=460.8 (M+H.sup.+).
Example 132
rac-N'-{2-[(7-Methoxy-5-methyl-2,3-dihydro-1H-inden-1-yl)amino]quinolin-6--
yl}-N,N-dimethylsulfamide
[0532] The title compound was prepared in accordance with the
general method described in example 66 from
dimethylsulfamoylchloride and
rac-N.sup.2-(7-methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine;
MS: m/e=427.6 (M+H.sup.+).
Example 133
1-(1-Cyanomethyl-piperidin-4-yl)-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-
-urea
[0533] Step A: Piperidin-4-yl-carbamic acid tert-butyl ester (CAS
no: 259180-66-0) (0.70 g, 0.0029 Mol) were dissolved in
HCl/Methanol 2.5 M (5 mL) and stirred at 40.degree. C. for 4 h.
Then the solvent was removed and the obtained crystals dried under
high vacuum. (4-Amino-piperidin-1-yl)-acetonitrile dihydrochloride
(0.6 g, 100%) was obtained as a white powder; MS: m/e=140.6
(M+H.sup.+).
[0534] Step B: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate,
(4-amino-piperidin-1-yl)-acetonitrile dihydrochlorid and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=441.8
(M+H.sup.+).
Example 134
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2,2,2-trifluoro-ethyl)-pip-
eridin-4-yl]-urea
[0535] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamine
hydrochloride (CAS no: 180869-49-2) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=484.8
(M+H.sup.+).
Example 135
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-methanesulfonyl-ethyl)-p-
iperidin-4-yl]-urea
[0536]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea
(0.05 g, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and
methylvinylsulfone (0.016 g, 0.15 mmol) were dissolved in
tetrahydrofuran (3 mL) and stirred at ambient temperature for 16 h.
Ethyl acetate (10 mL) was added to the reaction mixture and
everything subsequently washed with water. The organic phase was
dried over sodium sulfate, filtered and the filtrate evaporated.
The residue was subjected to column chromatography (basic silica
gel, ethyl acetate) to yield the title compound (0.026 g, 41%) as
an off-white solid; MS: m/e=508.8 (M+H.sup.+).
Example 136
2-(4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidin-1-yl)-N,-
N-dimethyl-acetamide
[0537]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea
(0.05 g, 0.12 mmol), 2-chloro-N,N-dimethylacetamide (0.023 mg, 0.18
mmol) and sodium carbonate (0.02 g, 0.18 mmol) were stirred at
ambient temperature for 16 h in N,N-dimethylformamide (3 mL). The
reaction mixture was evaporated. The residue was taken up in
dimethylsulfoxide (1 mL) and subjected to preparative HPLC to yield
the title compound (0.053 g, 87%) as a yellow oil; MS: m/e=487.8
(M+H.sup.+).
Example 137
1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinolin-
-6-yl]-urea
[0538]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea
(0.05 g, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and
2-bromoethanol (0.019 mL, 0.15 mmol) were dissolved in
tetrahydrofuran (3 mL) and stirred at 60.degree. C. for 7 h. The
reaction mixture was evaporated. The residue was subjected to
column chromatography (basic silica gel, methylene
chloride/methanol 19:1, 9:1) to yield the title compound (0.023 g,
41%) as a white solid; MS: m/e=446.8 (M+H.sup.+).
Example 138
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-carbamic acid isopropyl
ester
[0539] (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (0.07 g, 0.25
mmol), triethylamine (0.052 mL, 0.38 mmol) and isopropyl
chloroformate (1M solution in toluene) (0.281 mL, 0.28 mmol) were
dissolved in toluene (3 mL) and stirred at 60.degree. C. for 10 h.
The reaction mixture was diluted with water and extracted with
ethyl acetate (10 mL). The combined organic phases was dried over
sodium sulfate, filtered and the filtrate evaporated. The residue
was subjected to column chromatography (silica gel, heptane/ethyl
acetate, 9:1, 4:1, 3:1) to yield the title compound (0.026 g, 41%)
as a white foam; MS: m/e=361.7 (M+H.sup.+).
Example 139
rac-N-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin--
1-yl)-acetamide
[0540] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) and (4-methylpiperazinl-yl)-acetic acid; MS: m/e=446.1
(M+H.sup.+).
Example 140
rac-Cyclopropanecarboxylic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide
[0541] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) and cyclopropyl carboxylic acid; MS: m/e=374.4
(M+H.sup.+).
Example 141
rac-Cyclopropanecarboxylic acid
[2-(5-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide
[0542] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and
cyclopropyl carboxylic acid; MS: m/e=362.2 (M+H.sup.+).
Example 142
rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-1-
-yl)-acetamide
[0543] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and
(4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.3
(M+H.sup.+).
Example 143
rac-N.sup.2-(6-Fluoro-indan-1-yl)-quinoline-2,6-diamine
[0544] The title compound was prepared in accordance with the
general method described in example 2 from
2-chloro-6-nitro-quinoline and rac-6-fluoro-indan-1-ylamine (CAS
no: 168902-77-0); MS: m/e=294.3 (M+H.sup.+).
Example 144
rac-1-[2-(6-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea
[0545] The title compound was prepared in accordance with the
general method described in example 3 from
rac-N.sup.2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and
isopropyl isocyanate; MS: m/e=379.4 (M+H.sup.+).
Example 145
rac-N.sup.2-(7-Fluoro-indan-1-yl)-quinoline-2,6-diamine
[0546] Step A+B: rac-7-Fluoro-indan-1-ylamine was prepared in
accordance with the general method described in example 130, step A
and B from 7-fluoro-indan-1-one (CAS no: 651735-59-0); MS:
m/e=152.3 (M+H.sup.+).
[0547] Step C+D: The title compound was prepared in accordance with
the general method described in example 2 from
2-chloro-6-nitro-quinoline and rac-7-fluoro-indan-1-ylamine; MS:
m/e=294.3 (M+H.sup.+).
Example 146
rac-1-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-isopropyl-urea
[0548] The title compound was prepared in accordance with the
general method described in example 3 from
rac-N.sup.2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and
isopropyl isocyanate; MS: m/e=379.4 (M+H.sup.+).
Example 147
rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-isopropyl-piperazi-
n-1-yl)-acetamide
[0549] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and
(4-isopropyl-piperazin-1-yl)-acetic acid (CAS no: 95470-68-1); MS:
m/e=462.5 (M+H.sup.+).
Example 148
(1S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptane-5-sulfonic acid
[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-amide
[0550] The title compound was prepared in accordance with step C of
the general method described in example 76 from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) and
1-methyl-3-[(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)sulfonyl]-3(-
H)-imidazol-1-ium trifluoro-methanesulfonate; MS: m/e=467.0
(M+H.sup.+).
Example 149
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-thiourea
[0551] Step A: (R)-6-Amino-2-indanoyl-quinoline (1.2 g, 4.4 mmol)
was dissolved in 50 mL acetone. Benzoyl-isothiocyanate (749 mg, 4.6
mmol) was added and the reaction mixture was stirred at room
temperature overnight. The solvent was evaporated and the residue
was purified by column chromatography (silica gel,
dichloromethane/ethyl acetate 19:1).
1-Benzoyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-thiourea (1.55
g, 81%) was obtained as a light yellow foam; MS: m/e=439.1
(M+H.sup.+).
[0552] Step B:
1-Benzoyl-3-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-thiourea (1.5
g, 3.4 mmol) was suspended in 50 mL methanol. 4.1 mL 1N sodium
hydroxide solution was added and the reaction mixture was refluxed
for 2 h. The reaction mixture was diluted with 80 mL water and
extracted with dichloromethane (2.times.100 mL). The organic phases
were pooled, dried with sodium sulfate and evaporated. The residue
was recrystallized from dichloromethane and diethylether. The title
compound (660 mg, 58%) was obtained as an off-white solid; MS:
m/e=335.3 (M+H.sup.+).
Example 150
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea
hydroiodide
[0553] [2-((R)-Indan-1-ylamino)-quinolin-6-yl]-thiourea (600 mg,
1.8 mmol) was dissolved in 20 mL acetone and 10 mL tetrahydrofuran.
Methyliodide (306 mg, 2.2 mmol) was added and the reaction mixture
was stirred at room temperature for 3 h. The solvent was evaporated
and the residue was recrystallized from dichloromethane and
diethylether. The title compound (720 mg, 84%) was obtained as a
yellow solid; MS: m/e=349.4 (M+H.sup.+).
Example 151
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-morpholine-4-carboxamidine
[0554]
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea
hydroiodide (345 mg, 0.72 mmol) was dissolved in 10 mL ethanol.
Morpholine (350 mg, 4 mmol) was added and the reaction mixture was
refluxed overnight. The solvent was evaporated and the residue was
purified by column chromatography (silica gel,
dichloromethane/methanol 40:1). The title compound (144 mg, 51%)
was obtained as a light yellow foam; MS: m/e=388.3 (M+H.sup.+).
Example 152
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-N'-(1-methyl-piperidin-4-yl)-gua-
nidine
[0555] The title compound was prepared in accordance with the
general method 16 described in example 151 from
1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea
hydroiodide and 1-methylpiperidine-4-amine; MS: m/e=415.3
(M+H.sup.+).
Example 153
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-N-isopropyl-guanidine
[0556] The title compound was prepared in accordance with the
general method 16 described in example 151 from
1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea
hydroiodide and isopropylamine; MS: m/e=360.3 (M+H.sup.+).
Example 154
N-Cyclopropyl-N'-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-guanidine
[0557] The title compound was prepared in accordance with the
general method 16 described in example 151 from
1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-2-methyl-isothiourea
hydroiodide and cyclopropylamine; MS: m/e=358.4 (M+H.sup.+).
Example 155
rac-1-[2-(6-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperidi-
n-4-yl)-urea
[0558] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no: 127285-08-9)
and rac-N.sup.2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine; MS:
m/e=462.5 (M+H.sup.+).
Example 156
rac-1-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-(1-isopropyl-piperidi-
n-4-yl)-urea
[0559] The title compound was prepared in accordance with the
general method 4 described in example 16 from bis(trichloromethyl)
carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no: 127285-08-9)
and rac-N.sup.2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine; MS:
m/e=462.3 (M+H.sup.+).
Example 157
rac-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-carbamic acid
methyl ester
[0560] The title compound was obtained as a by-product in the above
described synthesis of example 156; MS: m/e=352.3 (M+H.sup.+).
Example 158
rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-morpholin-4-yl-acetam-
ide
[0561] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and
morpholin-4-yl-acetic acid; MS: m/e=421.2 (M+H.sup.+).
Example 159
rac-N-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-acetamide
[0562] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and acetic
acid; MS: m/e=334.4 (M-H.sup.+).
Example 160
rac-2-Cyclopropyl-N-[2-(5-fluoro-indan-1-ylamino)-quinolin-6-yl]-acetamide
[0563] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and
cyclopropyl acetic acid; MS: m/e=376.2 (M+H.sup.+).
Example 161
rac-N-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-1-
-yl)-acetamide
[0564] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and
(4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.4
(M+H.sup.+).
Example 162
rac-Cyclopropanecarboxylic acid
[2-(7-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide
[0565] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and
cyclopropyl acetic acid; MS: m/e=362.4 (M+H.sup.+).
Example 163
N.sup.2--(R)-Indan-1-yl-N6-morpholin-4-yl-quinoline-2,6-diamine
[0566] Step A: A stirred mixture of commercially available
6-bromo-2-chloro-quinoline (3.0 g, 12.4 mmol), commercially
available (R)-1-aminoindane (2.0 g, 15.0 mmol),
N-ethyl-diisopropylamine (2.4 g, 18.6 mmol) and
N-methyl-pyrrolidone (3 mL) was heated in a sealed tube for 24 h at
135.degree. C. The reaction mixture was poured into water (70 mL)
and extracted with diethyl ether (2.times.125 mL). The combined
organic layers were washed with water (2.times.150 mL), dried
(MgSO.sub.4) and evaporated. Further purification of the crude
product by column chromatography on silica gel (toluene/ethyl
acetate 9:1) and crystallization (diethyl ether/heptane) yielded
the title compound (3.39 mg, 81%) as off-white solid. MS (ISP)
339.0 (M+H.sup.+).
[0567] Step B: A mixture of
(6-bromo-quinolin-2-yl)-(R)-indan-1-yl-amine (339 mg, 1.0 mmol),
commercially available 4-amino-morpholine (204 mg, 2.0 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-butyl
X-PHOS) (68 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium
(0) (37 mg, 0.04 mmol), sodium tert.-butylate (106 mg, 1.1 mmol)
and dioxane (6 mL) was heated in a sealed tube at 120.degree. C.
for 18 h. The reaction mixture was purified by flash chromatography
on silica gel (ethyl acetate/heptane) and crystallization (diethyl
ether/heptane) to yield the title compound (72 mg, 20%) as
off-white solid. MS (ISP): m/e=361.3 (M+H.sup.+); m.p. 152.degree.
C.
Example 164
N.sup.2-(R)-Indan-1-yl-N6-(4-methyl-piperazin-1-yl)-quinoline-2,6-diamine
[0568] The title compound, yellow oil, MS (ISP): m/e=374.4
(M+H.sup.+), was prepared in accordance with the general method of
example 163, step B from
(6-bromo-quinolin-2-yl)-(R)-indan-1-yl-amine (see example 163, step
A) and commercially available 1-amino-4-methyl-piperazine.
Example 165
(R)-Indan-1-yl-[6-(4-methyl-piperazin-1-yl)-quinolin-2-yl]-amine
[0569] The title compound, brown oil, MS (ISP): m/e=359.3
(M+H.sup.+), was prepared in accordance with the general method of
example 163, step B from
(6-bromo-quinolin-2-yl)-(R)-indan-1-yl-amine (see example 163, step
A) and commercially available 1-methyl-piperazine.
Example 166
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-N',N''-diisopropyl-guanidine
[0570] (R)--N-2-indan-1-yl-quinoline-2,6-diamine (0.10 g, 0.36
mmol) and N,N'-diisopropylcarbodiimide (0.046 mg, 0.36 mmol) were
dissolved in toluene (3 mL) and stirred at 100.degree. C. for 16 h.
The reaction mixture was evaporated and the residue was subjected
to column chromatography (silica gel, heptane/ethyl acetate, 4:1,
2:1, 1:1) to yield the title compound (0.027 g, 19%) as a light
brown foam; MS: m/e=402.7 (M+H.sup.+).
Example 167
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-carbamic acid
1-methyl-piperidin-4-yl ester
[0571] The title compound was prepared in accordance with the
general method 11 described in example 138 from triethylamine,
4-chlorocarbonyloxy-1-methylpiperidine hydrochloride (CAS no:
127595-09-9) and (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine; MS:
m/e=215.3 (M+H.sup.+).
Example 168
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-9-isopropyl-9-aza-bic-
yclo[3.3.1]non-3-yl)-urea
[0572] Step A: 9-Isopropyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime: A
mixture of 9-isopropyl-9-aza-bicyclo[3.3.1]nonan-3-one (CAS no:
56258-85-6) (5.0 g, 28 mmol) in ethanol (125 mL) and pyridine (3.3
mL, 41 mmol) with hydroxylamine hydrochloride (2.03 g, 29 mmol) was
refluxed for 6 h. Cooled to 23.degree. C., the precipitate was
filtered off, washed with diethyl ether leaving a solid, which was
partitioned between dichloromethane and sodium carbonate solution,
the organic layers dried over Na.sub.2SO.sub.4, filtered and the
solvents evaporated to give the title compound as a white solid.
(4.43 g, 82%); MS: m/e=197.1 (M+H.sup.-).
[0573] Step B:
(3-exo)-9-Isopropyl-9-aza-bicyclo[3.3.1]non-3-ylamine
dihydrochloride: A solution of the above described
9-isopropyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime (1.96 g, 10 mmol)
was treated with sodium in pentanol, followed by aqueous workup and
HCl salt generation as described in Example 99 Step B. Obtained the
title compound as white crystals (2.41 g, 94%); MS: m/e=183.2
(M+H.sup.+).
[0574] Step C: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate (49 mg, 0.17 mmol), the above
described (3-exo)-9-isopropyl-9-aza-bicyclo[3.3.1]non-3-ylamine
dihydrochloride (93 mg, 0.363 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.363 mmol);
obtained as a white solid (74 mg, 42%); MS: m/e=484.3
(M+H.sup.+).
Example 169
1-((3-exo)-8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-((R)-indan-1-y-
lamino)-quinolin-6-yl]-1-methyl-urea
[0575] Step A:
(3-exo)-(8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-carbamic acid
ethyl ester: To a mixture of
(3-exo)-8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-ylamine
dihydrochloride (Example 99, Step B) (1.0 g, 4.18 mmol) and
K.sub.2CO.sub.3 (2.022 g, 14.63 mmol) in Methanol (10 mL) was added
ethyl chloroformate (0.44 mL, 4.59 mmol) and the mixture was
stirred at 23.degree. C. for 16 h. Added 15% NaOH solution, stirred
15 min and filtered the solids off, to the filtrate was added solid
Na.sub.2SO.sub.4, filtered and the solvents were evaporated to give
the title compound as a white solid. (0.91 g, 91%); MS: m/e=239.2
(M+H.sup.+).
[0576] Step B:
(3-exo)-(8-Cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-methyl-amine:
A mixture of the above described
(3-exo)-(8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-carbamic acid
ethyl ester (910 mg, 3.81 mmol) in tetrahydrofuran (10 mL) with
lithium aluminum hydride (362 mg, 9.54 mmol) was refluxed for 16 h.
Cooled to 0.degree. C., added water (0.362 mL), then at 23.degree.
C. 15% NaOH solution (1.086 mL), then again water (0.362 mL),
stirred at 23.degree. C. for 30 min, filtered the solid off, washed
with tetrahydrofuran, the filtrate was evaporated to give the the
title compound as a colorless oil (0.55 g, 80%); MS: m/e=150.3
(M-Me-NH.sub.2+H.sup.+).
[0577] Step C: The title compound was prepared in accordance with
the general method 4 described in example 16 from
bis(trichloromethyl) carbonate (352 mg, 5.81 mmol), the above
described
(3-exo)-(8-cyclopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-methyl-amine
(524 mg, 2.9 mmol) and
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (800 mg, 2.9 mmol);
obtained as a white solid (90 mg, 6%); MS: m/e=482.3
(M+H.sup.+).
Example 170
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-8-isopropyl-8-aza-bic-
yclo[3.2.1]oct-3-yl)-urea
[0578] Step A: 8-Isopropyl-8-aza-bicyclo[3.2.1]octan-3-one oxime: A
mixture of 8-isopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS no:
3423-28-7) (20.0 g, 120 mmol) in ethanol (500 mL) and pyridine
(14.5 mL, 179 mmol) with hydroxylamine hydrochloride (8.81 g, 127
mmol) was refluxed for 16 h. Cooled to 23.degree. C., the
precipitate was filtered off, washed with diethyl ether leaving a
solid, which was partitioned between dichloromethane and sodium
carbonate solution, the organic layers dried over Na.sub.2SO.sub.4,
filtered and the solvents evaporated to give the title compound as
a white solid. (17.7 g, 82%); MS: m/e=183.2 (M+H.sup.+).
[0579] Step B:
(3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-ylamine
dihydrochloride: A solution of the above described
8-isopropyl-8-aza-bicyclo[3.2.1]octan-3-one oxime (4.31 g, 24 mmol)
was treated with sodium in pentanol, followed by aqueous workup and
HCl salt generation as described in Example 99 Step B. Obtained the
title compound as white crystals (5.7 g, 100%); MS: m/e=169.2
(M+H.sup.+).
[0580] Step C:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((3-exo)-8-isopropyl-8-aza-bi-
cyclo[3.2.1]oct-3-yl)-urea: To a solution of
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (275 mg, 1.0 mmol)
and pyridine (80.5 uL, 1.0 mmol) in dichloromethane (5 mL) at
0.degree. C. was added 4-nitrophenyl chloroformate (202 mg, 1.0
mmol) and the mixture was stirred at 23.degree. C. for 1.5 h
resulting in a yellow suspension. Added the above described
(3-exo)-8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-ylamine
dihydrochloride (241 mg, 1.0 mmol) and diisopropylethylamine (600
uL, 3.5 mmol) and dichloromethane (2 mL) and the clear solution was
stirred at 23.degree. C. for 2 days. Diluted with ethyl acetate,
(150 mL), washed with 1 M Na.sub.2CO.sub.3-sol. (2.times.50 mL), 1
M NaOH-sol. (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4.
Removal of the solvent in vacuum left a brown foam, which after
silica gel column chromatography was crystallized from
dichloromethane/diethyl ether to give the title compound as a light
grey solid (160 mg, 34%); MS: m/e=470.5 (M+H.sup.+).
Example 171
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-carbamic acid methyl
ester
[0581] To a solution of
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (1.2 g, 4.36 mmol)
and pyridine (0.35 mL, 4.36 mmol) in dichloromethane (25 mL) at
0.degree. C. was added 4-nitrophenyl chloroformate (878 mg, 4.6
mmol) and the mixture was stirred at 23.degree. C. for 2 h
resulting in a yellow suspension. Added tetrahydrofuran, filtered
the solid off, dissolved in dichloromethane and methanol, coated on
silica gel. Removal of the solvent in vacuum left a brown foam,
which after silica gel column chromatography was crystallized from
dichloromethane/diethyl ether to give the title compound as a
yellow foam (500 mg, 34%); MS: m/e=334.2 (M+H.sup.+).
Example 172
rac-N.sup.2-(7-Methoxy-indan-1-yl)-quinoline-2,6-diamine
[0582] Step A: rac-7-Methoxy-indan-1-ylamine: A mixture of
7-methoxy-indan-1-one oxime (CAS no: 908108-58-7, (E)-oxime
179899-16-2) (4.59 g, 25.9 mmol) in ethanol (500 mL) with 10%
palladium on carbon (4.59 g) was hydrogenated at 23.degree. C. and
atmospheric pressure for 16 h. Filtered the catalyst off, washed
with ethanol, evaporated the filtrate totally and dried in high
vacuum to give the title compound as a brown oil (2.7 g, 64%); MS:
m/e=164.2 (M+H.sup.+).
[0583] Step B:
rac-(7-Methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine: A mixture
of 2-chloro-6-nitro-quinoline (1.8 g, 8.62 mmol) in
1-methyl-2-pyrrolidone (5 mL) with the above described
7-methoxy-indan-1-ylamine (1.69 g, 10.35 mmol) and
N-ethyldiisopropylamine (2.22 mL, 12.94 mmol) was stirred at
140.degree. C. for 2 h. Cooled to 23.degree. C., poured onto water
and extracted twice with ethyl acetate, dried over Na.sub.2SO.sub.4
and evaporated totally to give a crude product which was purified
by silica gel column chromatography with heptane/dichloromethane
followed by trituration with diethyl ether to give the title
compound as a yellow solid (2.3 g, 80%); MS: m/e=336.3
(M+H.sup.+).
[0584] Step C:
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine: Prepared
from the above described
rac-(7-methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine (2.3 g,
6.85 mmol) according to step B in general example 2 and obtained
the title compound as a light brown solid (1.5 g, 71%); MS:
m/e=306.2 (M+H.sup.+).
Example 173
rac-N.sup.2-(4-Methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
[0585] Step A: 4-Methoxy-benzofuran-3-one oxime: A mixture of
4-methoxy-benzofuran-3-one (CAS no: 7169-35-9) (4.9 g, 19 mmol),
sodium acetate (3.06 g, 38 mmol) and hydroxylamine hydrochloride
(2.58 g, 38 mmol) in ethanol (40 mL) was refluxed for 6 h. Cooled
to 23.degree. C., filtered the precipitate off, washed with ethanol
and dried in high vacuum to give the title compound as a white
solid (5.93 g, 100%); MS: m/e=180.2 (M+H.sup.+).
[0586] Step B: rac-4-Methoxy-2,3-dihydro-benzofuran-3-ylamine: A
mixture of the above described 4-methoxy-benzofuran-3-one oxime
(6.15 g, 34.3 mmol) in ethanol (500 mL) with 10% palladium on
carbon (6.15 g) was hydrogenated at 23.degree. C. and atmospheric
pressure for 18 h. Filtered the catalyst off, washed with ethanol,
evaporated the filtrate totally and dried in high vacuum to give
the title compound as a light yellow oil (3.65 g, 64%); MS:
m/e=166.2 (M+H.sup.-).
[0587] Step C:
rac-(4-Methoxy-2,3-dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine-
: A mixture of 2-chloro-6-nitro-quinoline (3.8 g, 18.2 mmol) in
1-methyl-2-pyrrolidone (5 mL) with the above described
rac-4-methoxy-2,3-dihydro-benzofuran-3-ylamine (3.61 g, 21.9 mmol)
and N-ethyldiisopropylamine (4.68 mL, 27.3 mmol) was stirred at
140.degree. C. for 2 h. Cooled to 23.degree. C., poured onto water
and extracted twice with ethyl acetate, dried over Na.sub.2SO.sub.4
and evaporated totally to give a crude product which was purified
by silica gel column chromatography with heptane/dichloromethane
followed by trituration with diethyl ether to give the title
compound as a yellow solid (4.0 g, 65%); MS: m/e=336.3
(M+H.sup.+).
[0588] Step D:
rac-N.sup.2-(4-Methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine-
: Prepared from the above described
rac-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine
(3.9 g, 11.6 mmol) according to step B in general example 2 and
obtained the title compound as a light brown solid (2.7 g, 76%);
MS: m/e=308.2 (M+H.sup.+).
Example 174
rac-N.sup.2-[4-(2-Methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-quinoline-2-
,6-diamine
[0589] Step A: 4-(2-Methoxy-ethoxy)-benzofuran-3-one: A mixture of
4-hydroxy-benzofuran-3-one (CAS no: 19278-81-0) (4.9 g, 9 mmol),
potassium carbonate (1.66 g, 12 mmol) and 2-bromoethyl methylether
(1.13 mL, 12 mmol) in N,N-dimethylformamide (20 mL) was stirred at
80.degree. C. for 1.5 h. Cooled to 23.degree. C., poured into 1 N
HCl, extracted four times with ethyl acetate, dried combined
organic layer over Na.sub.2SO.sub.4. Removal of the solvent in
vacuum left a yellow residue which was purified by silica gel
column chromatography with heptane/ethyl acetate to give the title
compound as a white solid (1.3 g, 63%); MS: m/e=177.2
(M-OMe+H.sup.+).
[0590] Step B: 4-(2-Methoxy-ethoxy)-benzofuran-3-one oxime: A
mixture of the above described
4-(2-methoxy-ethoxy)-benzofuran-3-one (1.9 g, 9 mmol), sodium
acetate (1.5 g, 19 mmol) and hydroxylamine hydrochloride (1.3 g, 19
mmol) in ethanol (15 mL) was refluxed for 4 h. Cooled to 23.degree.
C., filtered the precipitate off, washed with water and ethanol and
dried in high vacuum to give the title compound as a white solid
(1.45 g, 71%); MS: m/e=224.1 (M+H.sup.-).
[0591] Step C:
rac-4-(2-Methoxy-ethoxy)-2,3-dihydro-benzofuran-3-ylamine: A
mixture of the above described
4-(2-methoxy-ethoxy)-benzofuran-3-one oxime (1.19 g, 5 mmol) in
methanol (100 mL) and tetrahydrofuran (100 mL) with 10% palladium
on carbon (1.42 g) was hydrogenated at 23.degree. C. and
atmospheric pressure for 5 days. Filtered the catalyst off, washed
with tetrahydrofuran, evaporated the filtrate totally and dried in
high vacuum to give the title compound as a red oil (1.15 g, 90%,
ca. 90% purity, contains residual starting material); MS: m/e=193.1
(M-NH.sub.2+H.sup.+).
[0592] Step D:
rac-[4-(2-Methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-(6-nitro-quinolin--
2-yl)-amine: A mixture of 2-chloro-6-nitro-quinoline (1.04 g, 5.0
mmol) in 1-methyl-2-pyrrolidone (10 mL) with the above described
rac-4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-ylamine (1.14 g,
5.5 mmol) and N-ethyldiisopropylamine (1.27 mL, 7.5 mmol) was
stirred at 140.degree. C. for 2 h. Cooled to 23.degree. C., poured
onto water and extracted twice with ethyl acetate, dried over
Na.sub.2SO.sub.4 and evaporated totally to give a crude product
which was purified by silica gel column chromatography with
heptane/dichloromethane followed by trituration with diethyl ether
to give the title compound as an orange solid (1.24 g, 65%); MS:
m/e=382.3 (M+H.sup.-).
[0593] Step E:
rac-N.sup.2-[4-(2-Methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-quinoline--
2,6-diamine: Prepared from the above described
rac-[4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-(6-nitro-quinolin--
2-yl)-amine (1.24 g, 3.25 mmol) according to step B in general
example 2 and obtained the title compound as a light brown foam
(0.80 g, 70%); MS: m/e=352.3 (M+H.sup.+).
Example 175
rac-N.sup.2-(4-Ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
[0594] Step A: 4-Ethoxy-benzofuran-3-one oxime: A mixture of
4-ethoxy-benzofuran-3-one (CAS no: 7169-36-0) (4.18 g, 23.5 mmol),
sodium acetate (3.96 g, 48.3 mmol) and hydroxylamine hydrochloride
(3.34 g, 48.1 mmol) in ethanol (30 mL) was refluxed for 16 h.
Cooled to 23.degree. C., diluted with water (50 mL), filtered the
precipitate off, washed with water, ethanol and diethyl ether and
dried in high vacuum to give the title compound as a white solid
(4.2 g, 93%); MS: m/e=194.3 (M+H.sup.+).
[0595] Step B: rac-4-Ethoxy-2,3-dihydro-benzofuran-3-ylamine: A
mixture of the above described 4-ethoxy-benzofuran-3-one oxime (4.2
g, 21.7 mmol) in ethanol (200 mL) and tetrahydrofuran (200 mL) with
10% palladium on carbon (4.0 g) was hydrogenated at 23.degree. C.
and atmospheric pressure for 18 h. Filtered the catalyst off,
washed with ethanol, evaporated the filtrate totally and dried in
high vacuum to give the title compound as a light brown solid (3.7
g, 1:1 mixture of product and starting material); MS: m/e=163.3
(M+H.sup.+).
[0596] Step C:
rac-(4-Methoxy-2,3-dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine-
: A mixture of 2-chloro-6-nitro-quinoline (2.0 g, 9.6 mmol) in
1-methyl-2-pyrrolidone (5 mL) with the above described
rac-4-ethoxy-2,3-dihydro-benzofuran-3-ylamine (3.78 g, ca. 10 mmol,
max. 50% purity) and N-ethyldiisopropylamine (2.45 mL, 14.4 mmol)
was stirred at 140.degree. C. for 2 h. Cooled to 23.degree. C.,
poured onto water and extracted twice with ethyl acetate, dried
over Na.sub.2SO.sub.4 and evaporated totally to give a crude
product which was purified by silica gel column chromatography with
heptane/dichloromethane followed by trituration with diethyl ether
to give the title compound as a yellow solid (0.60 g, 18%); MS:
m/e=352.4 (M+H.sup.+).
[0597] Step D:
rac-N.sup.2-(4-Ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine:
Prepared from the above described
rac-(4-ethoxy-2,3-dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine
(0.6 g, 1.7 mmol) according to step B in general example 2 and
obtained the title compound as a light brown solid (0.26 g, 45%);
MS: m/e=322.2 (M+H.sup.+).
Example 176
3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-1-(1-isopropyl-piperidin-4-yl)-1-
-methyl-urea
[0598] The title compound was prepared from
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (275 mg, 1.0 mmol),
4-nitrophenyl chloroformate (202 mg, 1.0 mmol) and
(1-isopropyl-piperidin-4-yl)-methyl-amine dihydrochloride (CAS no:
of free base 503126-34-9) (229 mg, 1.0 mmol) in accordance with the
general method 4 described in example 170 step C and was obtained
as an off-white solid (186 mg, 41%); MS: m/e=458.3 (M+H.sup.+).
Example 177
3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-1-methyl-1-((3-exo)-8-methyl-8-a-
za-bicyclo[3.2.1]oct-3-yl)-urea
[0599] Step A:
(3-exo)-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-carbamic acid ethyl
ester: To a mixture of
(3-exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine dihydrochloride
(CAS no: 340682-25-9) (0.533 g, 2.5 mmol) and K.sub.2CO.sub.3
(1.036 g, 7.5 mmol) in water (5 mL) at 0.degree. C. was added ethyl
chloroformate (0.262 mL, 2.75 mmol) and the mixture was stirred at
23.degree. C. for 16 h. The reaction mixture saturated with solid
NaCl, extracted five times with dichloromethane, the combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and the
solvents evaporated to give the title compound as a white solid.
(0.257 g, 48%); MS: m/e=213.2 (M+H.sup.+).
[0600] Step B:
(3-exo)-Methyl-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine: A
mixture of the above described
(3-exo)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-carbamic acid ethyl
ester (257 mg, 1.21 mmol) in tetrahydrofuran (5 mL) with lithium
aluminum hydride (115 mg, 3.03 mmol) was refluxed for 16 h. Cooled
to 0.degree. C., added water (0.1 15 mL), then at 23.degree. C. 15%
NaOH solution (0.345 mL), then again water (0.115 mL), stirred at
23.degree. C. for 30 min, filtered the solid off, washed with
tetrahydrofuran, the filtrate was evaporated to give the the title
compound as a light yellow oil (0.175 g, 94%); MS: m/e=155.2
(M+H.sup.+).
[0601] Step C: The title compound was prepared from
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (79 mg, 0.285 mmol),
4-nitrophenyl chloroformate (58 mg, 0.285 mmol) and the above
described
(3-exo)-methyl-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine (44
mg, 0.285 mmol) in accordance with the general method 4 described
in example 170 step C and was obtained as an off-white solid (35
mg, 27%); MS: m/e=456.3 (M+H.sup.+).
Example 178
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((7-exo)-9-isopropyl-3-oxa-9-a-
za-bicyclo[3.3.1]non-7-yl)-urea
[0602] Step A: 9-Isopropyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one
oxime: A mixture of
9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (CAS no:
99189-30-7)(1.25 g, 6.82 mmol) in ethanol (40 mL) and pyridine (0.8
mL, 10.2 mmol) with hydroxylamine hydrochloride (0.5 g, 7.23 mmol)
was refluxed for 6 h. Cooled to 23.degree. C., evaporated all
volatiles, partitioned the residue between dichloromethane and
sodium carbonate solution, reextracted the aqueous layer with
tetrahydrofuran/ethyl acetate, all combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and the solvents evaporated
to give the title compound as a dark brown solid. (1.0 g, 74%); MS:
m/e=199.1 (M+H.sup.+).
[0603] Step B:
(7-exo)-9-Isopropyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-ylamine
dihydrochloride: A solution of the above described
9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one oxime (0.99 g,
4.99 mmol) was treated with sodium in pentanol, followed by aqueous
workup and HCl salt generation as described in Example 99 Step B.
Obtained the title compound as an off-white solid (0.69 g, 54%);
MS: m/e=185.2 (M+H.sup.+).
[0604] Step C:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-((7-exo)-9-isopropyl-3-oxa-9--
aza-bicyclo[3.3.1]non-7-yl)-urea: The title compound was prepared
from (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (275 mg, 1.0
mmol), 4-nitrophenyl chloroformate (202 mg, 1.0 mmol) and the above
described
(7-exo)-9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-ylamine
dihydrochloride (257 mg, 1.0 mmol) in accordance with the general
method 4 described in example 170 step C and was obtained as an
off-white solid (109 mg, 22%); MS: m/e=486.2 (M+H.sup.+).
Example 179
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(7-methoxy-indan-1-ylamino)-quinol-
in-6-yl]-1-methyl-urea
[0605] The title compound was prepared from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) (153 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5
mmol) and (1-isopropyl-piperidin-4-yl)-methyl-amine dihydrochloride
(CAS no: of free base 503126-34-9) (115 mg, 0.5 mmol) in accordance
with the general method 4 described in example 170 step C and was
obtained as an off-white solid (122 mg, 50%); MS: m/e=488.2
(M+H.sup.+).
Example 180
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benzofuran--
3-ylamino)-quinolin-6-yl]-urea
[0606] The title compound was prepared from
rac-N.sup.2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 173) (200 mg, 0.62 mmol), 4-nitrophenyl chloroformate (125
mg, 0.62 mmol) and 1-isopropyl-piperidin-4-ylamine dihydrochloride
(CAS no: 534596-29-7) (140 mg, 0.65 mmol) in accordance with the
general method 4 described in example 170 step C and was obtained
as an off-white solid (190 mg, 61%); MS: m/e=476.2 (M+H.sup.+).
Example 181
rac-1-[2-(4-Ethoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-3-(1-i-
sopropyl-piperidin-4-yl)-urea
[0607] The title compound was prepared from
rac-N.sup.2-(4-ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 175) (200 mg, 0.62 mmol), 4-nitrophenyl chloroformate (125
mg, 0.62 mmol) and 1-isopropyl-piperidin-4-ylamine dihydrochloride
(CAS no: 534596-29-7) (134 mg, 0.62 mmol) in accordance with the
general method 4 described in example 170 step C and was obtained
as an off-white solid (190 mg, 62%); MS: m/e=490.1 (M+H.sup.+).
Example 182
rac-1-(1-Isopropyl-piperidin-4-yl)-3-{2-[4-(2-methoxy-ethoxy)-2,3-dihydro--
benzofuran-3-ylamino]-quinolin-6-yl}-urea
[0608] The title compound was prepared from
rac-N.sup.2-[4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-quinoline--
2,6-diamine (Example 174) (200 mg, 0.57 mmol), 4-nitrophenyl
chloroformate (115 mg, 0.57 mmol) and
1-isopropyl-piperidin-4-ylamine dihydrochloride (CAS no:
534596-29-7) (122 mg, 0.57 mmol) in accordance with the general
method 4 described in example 170 step C and was obtained as an
off-white solid (210 mg, 71%); MS: m/e=520.5 (M+H.sup.+).
Example 183
rac-N-[2-(4-Methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-2-(4--
methyl-piperazin-1-yl)-acetamide
[0609] The title compound was prepared from
rac-N.sup.2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 173) (150 mg, 0.59 mmol) and commercially available
(4-methyl-piperazin-1-yl)-acetic acid (77 mg, 0.68 mmol) in
accordance with the general method 14 described in example 119 and
was obtained as an off-white solid (210 mg, 96%); MS: m/e=448.3
(M+H.sup.+).
Example 184
rac-N-[2-(4-Ethoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-2-(4-m-
ethyl-piperazin-1-yl)-acetamide
[0610] The title compound was prepared from
rac-N.sup.2-(4-ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 175) (200 mg, 0.49 mmol) and commercially available
(4-methyl-piperazin-1-yl)-acetic acid (74 mg, 0.65 mmol) in
accordance with the general method 14 described in example 119 and
was obtained as an off-white solid (200 mg, 93%); MS: m/e=462.2
(M+H.sup.+).
Example 185
rac-N-{2-[4-(2-Methoxy-ethoxy)-2,3-dihydro-benzofuran-3-ylamino]-quinolin--
6-yl}-2-(4-methyl-piperazin-1-yl)-acetamide
[0611] The title compound was prepared from
rac-N.sup.2-[4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-quinoline--
2,6-diamine (Example 174) (200 mg, 0.4 mmol) and commercially
available (4-methyl-piperazin-1-yl)-acetic acid (68 mg, 0.6 mmol)
in accordance with the general method 14 described in example 119
and was obtained as an off-white solid (160 mg, 76%); MS: m/e=492.3
(M+H.sup.+).
Example 186
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(7-methoxy-i-
ndan-1-ylamino)-quinolin-6-yl]-urea
[0612] The title compound was prepared from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) (153 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5
mmol) and (3-exo)-8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-ylamine
dihydrochloride (Example 170 step B) (121 mg, 0.5 mmol) in
accordance with the general method 4 described in example 170 step
C and was obtained as an off-white solid (42 mg, 17%); MS:
m/e=500.1 (M+H.sup.+).
Example 187
rac-3-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-1-(1-isopropyl-piperidi-
n-4-yl)-1-methyl-urea
[0613] The title compound was prepared from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine (Example
106) (200 mg, 0.681 mmol), 4-nitrophenyl chloroformate (137 mg,
0.681 mmol) and (1-isopropyl-piperidin-4-yl)-methyl-amine
dihydrochloride (CAS no: of free base 503126-34-9) (156 mg, 0.681
mmol) in accordance with the general method 4 described in example
170 step C and was obtained as an off-white solid (260 mg, 80%);
MS: m/e=476.3 (M+H.sup.+).
Example 188
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(7-methoxy-i-
ndan-1-ylamino)-quinolin-6-yl]-1-methyl-urea
[0614] Step A:
(3-exo)-(8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-carbamic acid
ethyl ester: To a mixture of
(3-exo)-8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-ylamine
dihydrochloride (Example 170 step B) (1.2 mg, 5.0 mmol) and
K.sub.2CO.sub.3 (2.07 g, 15 mmol) in water (10 mL) at 0.degree. C.
was added ethyl chloroformate (0.524 mL, 5.5 mmol) and the mixture
was stirred at 23.degree. C. for 16 h. The reaction mixture
saturated with solid sodium chloride, extracted five times with
dichloromethane, the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the solvents evaporated to give the
title compound as a light yellow solid. (0.820 g, 68%); MS:
m/e=241.2 (M+H.sup.+).
[0615] Step B:
(3-exo)-(8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-methyl-amine: A
mixture of the above described
(3-exo)-(8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-carbamic acid
ethyl ester (900 mg, 3.75 mmol) in tetrahydrofuran (15 mL) with
lithium aluminum hydride (355 mg, 9.36 mmol) was refluxed for 16 h.
Cooled to 0.degree. C., added water (0.355 mL), then at 23.degree.
C. 15% NaOH solution (1.065 mL), then again water (0.355 mL),
stirred at 23.degree. C. for 30 min, filtered the solid off, washed
with tetrahydrofuran, the filtrate was evaporated to give the the
title compound as a light yellow oil (0.680 g, 100%); MS: m/e=183.2
(M+H.sup.+).
[0616] Step C: The title compound was prepared from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) (153 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5
mmol) and the above described
(3-exo)-(8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-methyl-amine (91
mg, 0.5 mmol) in accordance with the general method 4 described in
example 170 step C and was obtained as a yellow solid (68 mg, 26%);
MS: m/e=514.2 (M+H.sup.+).
Example 189
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamino-
)-quinolin-6-yl]-urea
[0617] The title compound was prepared from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) (200 mg, 0.655 mmol), 4-nitrophenyl chloroformate (132 mg,
0.655 mmol) and commercially available 4-amino-1-piperidine ethanol
(94 mg, 0.655 mmol) in accordance with the general method 4
described in example 170 step C and was obtained as an off-white
solid (160 mg, 26%); MS: m/e=476.2 (M+H.sup.+).
Example 190
rac-Cyclopropanecarboxylic acid
[2-(6-fluoro-indan-1-ylamino)-quinolin-6-yl]-amide
[0618] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N.sup.2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and
cyclopropanecarboxylic acid; MS: m/e=362.4 (M+H.sup.-).
Example 191
rac-1-[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-
-1-ylamino)-quinolin-6-yl]-1-methyl-urea
[0619] Step A:
[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-carbamic acid ethyl
ester: A mixture of commercially available ethyl
piperidin-4-ylcarbamate (2.067 g, 12 mmol) and isobutylene oxide
(868 mg, 12 mmol) in ethanol (15 mL) was irradiated in a microwave
apparatus at 110.degree. C. for 90 min. Purification by silica gel
column chromatography with ethyl acetate gave the title compound as
a colorless oil (2.838 g, 97%); MS: m/e=245.3 (M+H.sup.+).
[0620] Step B:
2-Methyl-1-(4-methylamino-piperidin-1-yl)-propan-2-ol: A mixture of
the above described
[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-carbamic acid ethyl
ester (2.35 g, 10 mmol) in tetrahydrofuran (40 mL) with lithium
aluminum hydride (913 mg, 24 mmol) was refluxed for 16 h. Cooled to
0.degree. C., added water (0.913 mL), then at 23.degree. C. 15%
NaOH solution (2.739 mL), then again water (0.913 mL), stirred at
23.degree. C. for 30 min, filtered the solid off, washed with
tetrahydrofuran, the filtrate was evaporated to give the the title
compound as a colorless oil (1.80 g, 100%); MS: m/e=187.2
(M+H.sup.+).
[0621] Step C: The title compound was prepared from
rac-N.sup.2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example
172) (305 mg, 1.0 mmol), 4-nitrophenyl chloroformate (202 mg, 1.0
mmol) and the above
2-methyl-1-(4-methylamino-piperidin-1-yl)-propan-2-ol (186 mg, 1.0
mmol) in accordance with the general method 4 described in example
170 step C and was obtained as an off-white solid (286 mg, 55%);
MS: m/e=518.2 (M+H.sup.+).
Example 192
1-[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino-
)-quinolin-6-yl]-1-methyl-urea
[0622] The title compound was prepared from
(R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (275 mg, 1.0 mmol),
4-nitrophenyl chloroformate (202 mg, 1.0 mmol) and
2-methyl-1-(4-methylamino-piperidin-1-yl)-propan-2-ol (Example 191
step B) (186 mg, 1.0 mmol) in accordance with the general method 4
described in example 170 step C and was obtained as an off-white
solid (263 mg, 54%); MS: m/e=488.1 (M+H.sup.+).
Example 193
rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benzofuran--
3-ylamino)-quinolin-6-yl]-1-methyl-urea
[0623] The title compound was prepared from
rac-N.sup.2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 173) (153 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101
mg, 0.5 mmol) and (1-isopropyl-piperidin-4-yl)-methyl-amine
dihydrochloride (CAS no: of free base 503126-34-9) (115 mg, 0.5
mmol) in accordance with the general method 4 described in example
170 step C and was obtained as an off-white solid (134 mg, 55%);
MS: m/e=490.1 (M+H.sup.+).
Example 194
rac-1-((3-exo)-8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-[2-(4-methoxy-2-
,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-methyl-urea
[0624] The title compound was prepared from rac
N.sup.2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 173) (154 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101
mg, 0.5 mmol) and
(3-exo)-(8-isopropyl-8-aza-bicyclo[3.2.1]oct-3-yl)-methyl-amine
(Example 188 step B) (91 mg, 0.5 mmol) in accordance with the
general method 4 described in example 170 step C and was obtained
as an off-white solid (160 mg, 62%); MS: m/e=516.0 (M+H.sup.+).
Example 195
rac-Cyclopropanecarboxylic acid
[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-amide
[0625] The title compound was prepared from
rac-N.sup.2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 173) (154 mg, 0.5 mmol) and commercially available
cyclopropanecarboxylic acid (40 ul, 0.5 mmol) in accordance with
the general method 14 described in example 119 and was obtained as
an off-white solid (68 mg, 36%); MS: m/e=376.3 (M+H.sup.+).
Example 196
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-acetamide
[0626] (R)--N.sup.2-indan-1-yl-quinoline-2,6-diamine (551 mg, 2
mmol) was dissolved in acetic acid (5 mL) then acetic anhydride
(378 ul, 4 mmol) was added and the mixture was stirred at for 16 h.
The reaction mixture was extracted with ethyl acetate and sat.
NaHCO.sub.3-sol., the organic layers were combined, dried over
MgSO.sub.4, filtered and the solvents evaporated to give the title
compound as a light brown foam (640 mg, 100%); MS: m/e=318.1
(M+H.sup.+).
Example 197
rac-1-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-3-[1-(2-hydroxy-ethyl)--
piperidin-4-yl]-urea
[0627] The title compound was prepared from
rac-N.sup.2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine (Example
106) (240 mg, 0.818 mmol), 4-nitrophenyl chloroformate (165 mg,
0.818 mmol) and commercially available 4-amino-1-piperidine-ethanol
(118 mg, 0.818 mmol) in accordance with the general method 4
described in example 170 step C and was obtained as an off-white
solid (54 mg, 14%); MS: m/e=464.2 (M+H.sup.+).
Example 198
(-)-N-[2-((S)-4-Methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-2-
-(4-methyl-piperazin-1-yl)-acetamide
[0628]
rac-N-[2-(4-Methoxy-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl-
]-2-(4-methyl-piperazin-1-yl)-acetamide (Example 183) was separated
on chiral preparative HPLC using 30% ethanol in heptane. Obtained
as a white solid (71 mg).
Example 199
rac-1-[1-(2-Hydroxy-2-methyl-propyl)-piperidin-4-yl]-3-[2-(4-methoxy-2,3-d-
ihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-methyl-urea
[0629] The title compound was prepared from
rac-N.sup.2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 173) (154 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101
mg, 0.5 mmol) and
2-methyl-1-(4-methylamino-piperidin-1-yl)-propan-2-ol (Example 191
step B) (93 mg, 0.5 mmol) in accordance with the general method 4
described in example 170 step C and was obtained as a white solid
(39 mg, 15%); MS: m/e=520.0 (M+H.sup.+).
Example 200
rac-N-2-(6-Fluoro-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
[0630] Step A: 6-Fluoro-benzofuran-3-one oxime: A mixture of
6-fluoro-benzofuran-3-one (CAS 351528-80-8) (5.93 g, 39 mmol),
sodium acetate (6.587 g, 80 mmol) and hydroxylamine hydrochloride
(5.553 g, 80 mmol) in ethanol (70 ml) was refluxed for 4 h. Cooled
to 23.degree. C., filtered the precipitate off, washed with aqueous
ethanol and dried in high vacuum to give the title compound as a
white solid (5.19 g, 80%, HPLC 1.489 min); MS (ISN) m/e=168.1
[(M-H).sup.-].
[0631] Step B: rac-6-Fluoro-2,3-dihydro-benzofuran-3-ylamine: A
mixture of the above described 6-fluoro-benzofuran-3-one oxime
(5.38 g, 32 mmol; HPLC 1.489 min) and Raney-Nickel (2.4 g) in
tetrahydrofuran (125 mL) and methanol (125 mL) was hydrogenated at
100 bar hydrogen-pressure at 50.degree. C. for 18 h. Filtered the
catalyst off, washed with methanol and tetrahydrofuran, all
volatiles very removed in vacuum to give the crude product which
was purified by Si--NH.sub.2 column chromatography with
n-heptane/ethyl acetate to give the title compound as a light brown
liquid (1.65 g, 34%, HPLC 0.367 min 100%), MS (ISP) m/e=154.0
[(M+H).sup.+].
[0632] Step C:
rac-(6-Fluoro-2,3-dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine:
A mixture of 2-chloro-6-nitro-quinoline (1.6 g, 7.67 mmol) in
N-methyl-2-pyrrolidinone (15 ml) with the above described
rac-6-fluoro-2,3-dihydro-benzofuran-3-ylamine (1.3 g, 8.43 mmol)
and N-ethyldiisopropylamine (1.96 ml, 11.5 mmol) was stirred at
140.degree. C. for 2 h. Cooled to room temperature, poured onto
water and extracted twice with Ethyl acetate, dried over sodium
sulfate and evaporated totally to give a crude product which was
purified by silica gel column chromatography with
heptane/dichloromethane followed by trituration with diethyl ether
to give the title compound as a yellow solid (1.0 g, 40%); MS (ISP)
m/e=326.2 (M+H.sup.+).
[0633] Step D:
rac-N-2-(6-Fluoro-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine:
Prepared from the above described
rac-(6-fluoro-2,3-dihydro-benzofuran-3-yl)-(6-nitro-quinolin-2-yl)-amine
(1.0 g, 3.07 mmol) according to step B in general example 2 and
obtained the title compound as a grey solid (0.56 g, 62%); MS (ISP)
m/e=296.1 (M+H.sup.+).
Example 201
rac-N-[2-(7-Fluoro-indan-1-ylamino)-quinolin-6-yl]-2-methoxy-acetamide
[0634] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N-2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and methoxy
acetic acid; MS: m/e=366.3 (M+H.sup.+).
Example 202
rac-3-[2-(6-Fluoro-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-(1-i-
sopropyl-piperidin-4-yl)-1-methyl-urea
[0635] Prepared from
rac-N-2-(6-fluoro-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 200) (200 mg, 0.67 mmol), 4-nitrophenyl chloroformate (137
mg, 0.67 mmol) and (1-isopropyl-piperidin-4-yl)-methyl-amine
dihydrochloride (CAS of free base 503126-34-9) (140 mg, 0.65 mmol)
and diisopropylethyl amine (410 ul, 2.37 mmol) according to the
procedure described for Example 170 step C. Obtained the title
compound as an off-white solid (250 mg, 77%), MS (ISP) m/e=478.1
[(M+H).sup.+].
Example 203
rac-N-[2-(6-Fluoro-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-2-(4-m-
ethyl-piperazin-1-yl)-acetamide
[0636] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N-2-(6-fluoro-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 200) (320 mg, 1.08 mmol) and
(4-methylpiperazin-1-yl)-acetic acid (171 mg, 1.08 mmol). Obtained
as an off-white foam (410 mg, 87%), MS (ISP) m/e=436.2
(M+H.sup.-).
Example 204
(-)-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benzofuran--
3-ylamino)-quinolin-6-yl]-1-methyl-urea
[0637]
Rac-1-(1-Isopropyl-piperidin-4-yl)-3-[2-(4-methoxy-2,3-dihydro-benz-
ofuran-3-ylamino)-quinolin-6-yl]-1-methyl-urea (Example 193) was
separated on chiral preparative HPLC using 30% ethanol in heptane.
Obtained as a light brown solid (43 mg).
Example 205
1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinolin-
-6-yl]-1-methyl-urea
[0638] Step A: 2-(4-Methylamino-piperidin-1-yl)-ethanol: To a
solution of [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid
tert-butyl ester (CAS m 558443-53-1) (5.71 g, 23 mmol) in
tetrahydrofuran (100 ml) at 23.degree. C. was added in portions
lithium aluminum hydride (2.66 g, 70 mmol) and the mixture was
stirred at 70.degree. C. for 18 h. Then the reaction was cooled to
0.degree. C., water (2.66 ml) was added very slowly, then NaOH 15%
(7.98 ml) and water (2.66 ml). The mixture was stirred at
23.degree. C. for 1.5 h, the precipitate was filtered off, washed
with tetrahydrofuran and the organic layer was evaporated totally
to give the title compound as a white solid (3.7 g, 100%), MS (ISP)
m/e=159.3 [(M+H).sup.+].
[0639] Step B:
1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-((R)-indan-1-ylamino)-quinoli-
n-6-yl]-1-methyl-urea: Prepared from
(R)--N-2-indan-1-yl-quinoline-2,6-diamine (Example 2) (200 mg,
0.726 mmol), 4-nitrophenyl chloroformate (146 mg, 0.726 mmol) and
the above described 2-(4-methylamino-piperidin-1-yl)-ethanol (115
mg, 0.726 mmol) and diisopropylethyl amine (432 ul, 2.54 mmol)
according to the procedure described for Example 170 step C.
Obtained the title compound as an off-white solid (230 mg, 69%), MS
(ISP) m/e=460.2 [(M+H).sup.+].
Example 206
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(7-methoxy-indan-1-ylamino-
)-quinolin-6-yl]-1-methyl-urea
[0640] Prepared from
rac-N-2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172)
(200 mg, 0.655 mmol), 4-nitrophenyl chloroformate (132 mg, 0.655
mmol) and the 2-(4-methylamino-piperidin-1-yl)-ethanol (Example 205
step A) (104 mg, 0.655 mmol) and diisopropylethyl amine (390 ul,
2.29 mmol) according to the procedure described for Example 170
step C. Obtained the title compound as an off-white solid (250 mg,
78%), MS (ISP) m/e=490.4 [(M+H).sup.-].
Example 207
rac-1-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-3-[2-(4-methoxy-2,3-dihydro-ben-
zofuran-3-ylamino)-quinolin-6-yl]-1-methyl-urea
[0641] Prepared from
rac-N-2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 173) (200 mg, 0.651 mmol), 4-nitrophenyl chloroformate
(131 mg, 0.651 mmol) and the
2-(4-methylamino-piperidin-1-yl)-ethanol (Example 205 step A) (103
mg, 0.651 mmol) and diisopropylethyl amine (388 ul, 2.28 mmol)
according to the procedure described for Example 170 step C.
Obtained the title compound as an off-white solid (230 mg, 72%), MS
(ISP) m/e=492.3 [(M+H).sup.-].
Example 208
rac-3-[2-(5-Fluoro-indan-1-ylamino)-quinolin-6-yl]-1-[1-(2-hydroxy-ethyl)--
piperidin-4-yl]-1-methyl-urea
[0642] Prepared from
rac-N-2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine (Example 106)
(200 mg, 0.682 mmol), 4-nitrophenyl chloroformate (137 mg, 0.682
mmol) and the 2-(4-methylamino-piperidin-1-yl)-ethanol (Example 205
step A) (108 mg, 0.682 mmol) and diisopropylethyl amine (406 ul,
2.39 mmol) according to the procedure described for Example 170
step C. Obtained the title compound as an off-white solid (240 mg,
74%), MS (ISP) m/e=478.4 [(M+H).sup.-].
Example 209
rac-3-[2-(6-Fluoro-2,3-dihydro-benzofuran-3-ylamino)-quinolin-6-yl]-1-[1-(-
2-hydroxy-ethyl)-piperidin-4-yl]-1-methyl-urea
[0643] Prepared from
rac-N-2-(6-fluoro-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine
(Example 200) (200 mg, 0.677 mmol), 4-nitrophenyl chloroformate
(137 mg, 0.677 mmol) and the
2-(4-methylamino-piperidin-1-yl)-ethanol (Example 205 step A) (107
mg, 0.677 mmol) and diisopropylethyl amine (400 ul, 2.37 mmol)
according to the procedure described for Example 170 step C.
Obtained the title compound as an off-white foam (230 mg, 71%), MS
(ISP) m/e=480.1 [(M+H).sup.-].
Example 210
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2-(4-methyl-piperazin-1-yl)-acet-
amide
[0644] The title compound was prepared in accordance with the
general method 14 described in example 119
from(R)--N-2-indan-1-yl-quinoline-2,6-diamine (Example 2) (275 mg,
1.0 mmol) and (4-methylpiperazin-1-yl)-acetic acid (158 mg, 1.0
mmol). Obtained as a light red foam (339 mg, 82%), MS (ISP)
m/e=416.4 (M+H.sup.+).
Example 211
N-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-2,2-dimethyl-propionamide
[0645] (R)--N-2-Indan-1-yl-quinoline-2,6-diamine (Example 2) (275
mg, 1.0 mmol) was dissolved in pyridine (3 ml), pivaloyl chloride
(123 ul, 1 mmol) was added and the mixture was stirred at
23.degree. C. for 18 h. All volatiles were removed in vacuum, the
residue was directly subjected to chromatography with
n-heptane/ethyl acetate to give the title compound as a light brown
solid (182 mg, 51%), MS (ISP) m/e=360.2 (M+H.sup.+).
Example 212
rac-N-[2-(7-Methoxy-indan-1-ylamino)-quinolin-6-yl]-2-morpholin-4-yl-aceta-
mide
[0646] The title compound was prepared in accordance with the
general method 14 described in example 119 from
rac-N-2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine and
morpholin-4-yl-acetic acid; MS: m/e=431.5 (M-H.sup.-).
Example 213
rac-2-(2-Dimethylamino-ethylamino)-N-[2-(7-methoxy-indan-1-ylamino)-quinol-
in-6-yl]-acetamide
[0647] Step A:
rac-2-Chloro-N-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-acetamide:
rac-N-2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (1.0 g, 3.3
mmol) was dissolved in 25 mL ethyl acetate and 25 mL saturated
sodium bicarbonate solution. Chloroacetyl chloride (407 mg, 3.6
mmol) was added at 0.degree. C. and the reaction mixture was
stirred at room temperature for 1 h. The mixture was extracted
three times with ethyl acetate and combined organic layers were
dried over sodium sulfate. Removal of the solvent in vacuum left a
yellow residue which was purified by silica gel column
chromatography with heptane/ethyl acetate to give the title
compound as a white solid (611 mg, 49%). MS (ISN) m/e=380.5
[(M-H).sup.-].
[0648] Step B:
rac-2-(2-Dimethylamino-ethylamino)-N-[2-(7-methoxy-indan-1-ylamino)-quino-
lin-6-yl]-acetamide:
rac-2-Chloro-N-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-acetamide
(150 mg, 0.39 mmol) was suspended N,N-dimethylethylendiamine (693
mg, 7.9 mmol) and placed in an ultrasound bath for 4 min. The
mixture was diluted with 5 mL saturated sodium bicarbonate solution
and was extracted three times with ethyl acetate and combined
organic layers were dried over sodium sulfate. Removal of the
solvent in vacuum left a yellow residue which was purified by
silica gel column chromatography with dichloromethane/methanol to
give the title compound as a white foam (149 mg, 87%). MS (ISN)
m/e=432.5 [(M-H).sup.-].
Example 214
rac-2-(4-Cyclopropyl-piperazin-1-yl)-N-[2-(7-methoxy-indan-1-ylamino)-quin-
olin-6-yl]-acetamide
[0649] The title compound was prepared in accordance with the
general method 14 described in example 213 from
rac-N-2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine and,
chloroacetyl chloride and 1-cyclopropylpiperazine; MS: m/e=472.3
(M+H.sup.+).
* * * * *